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Bibliography on: Alzheimer Disease — Treatment

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 22 Oct 2020 at 01:32 Created: 

Alzheimer Disease — Treatment

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: alzheimer[TIAB] AND treatment[TIAB] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2020-10-21

Lam AD, J Noebels (2020)

Night Watch on the Titanic: Detecting Early Signs of Epileptogenesis in Alzheimer Disease.

Epilepsy currents [Epub ahead of print].

Aberrant cortical network excitability is an inextricable feature of Alzheimer disease (AD) that can negatively impact memory and accelerate cognitive decline. Surface electroencephalogram spikes and intracranial recordings of nocturnal silent seizures in human AD, coupled with the abnormal neural synchrony that precedes development of behavioral seizures in mouse AD models, build the case for epileptogenesis as an early therapeutic target for AD. Since most individuals with AD do not develop overt seizures, leveraging functional biomarkers of epilepsy risk to stratify a heterogeneous AD patient population for treatment is research priority for successful clinical trial design. Who will benefit from antiseizure interventions, which one, and when should it begin?

RevDate: 2020-10-20

Khazaei H, Pesce M, Patruno A, et al (2020)

Medicinal plants for diabetes associated neurodegenerative diseases: A systematic review of preclinical studies.

Phytotherapy research : PTR [Epub ahead of print].

Diabetes mellitus is a metabolic defect with many complications for the patients. Deaths due to diabetes and its complications are increasing, and one of the most serious consequences are the neurological disorders. Chemical treatments have irreversible side effect and therefore the aim of this study is to evaluate the medicinal plants used for treatment of cognitive impairments and neurodegenerative diseases associated with diabetes in 2004-2020 period. Electronic databases used were PubMed, Scopus and Cochrane library. The keywords used were "diabetes," "plant," "herb," "neurodegenerative," "neurodegeneration," "cognitive," "cognition," "Alzheimer," "dementia." The non-English articles, repetitive articles and review studies were excluded. From total of 3,590 results, 58 articles are included in the study. The results show that many chemical treatments considered for this disease simply control hyperglycemia, but cannot improve the complications of diabetes. Herbal medicine could be more effective due to the high antioxidant activity of some medicinal plants. Biologically active substances of medicinal plants can improve the neurological disorders caused by diabetes via several pathways. The most important pathway is related to antioxidant properties. Other pathways include antiinflammatory, anti-apoptotic, neurotoxicity inhibition, neuronal death, increasing the uptake of glucose by cells and improve neurotransmitters levels involved in learning and memory.

RevDate: 2020-10-20

Tsou AY, Bulova P, Capone G, et al (2020)

Medical Care of Adults With Down Syndrome: A Clinical Guideline.

JAMA, 324(15):1543-1556.

Importance: Down syndrome is the most common chromosomal condition, and average life expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite the unique clinical comorbidities among adults with Down syndrome, there are no clinical guidelines for the care of these patients.

Objective: To develop an evidence-based clinical practice guideline for adults with Down syndrome.

Evidence Review: The Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome Workgroup (n = 13) developed 10 Population/Intervention/ Comparison/Outcome (PICO) questions for adults with Down syndrome addressing multiple clinical areas including mental health (2 questions), dementia, screening or treatment of diabetes, cardiovascular disease, obesity, osteoporosis, atlantoaxial instability, thyroid disease, and celiac disease. These questions guided the literature search in MEDLINE, EMBASE, PubMed, PsychINFO, Cochrane Library, and the TRIP Database, searched from January 1, 2000, to February 26, 2018, with an updated search through August 6, 2020. Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework, in January 2019, the 13-member Workgroup and 16 additional clinical and scientific experts, nurses, patient representatives, and a methodologist developed clinical recommendations. A statement of good practice was made when there was a high level of certainty that the recommendation would do more good than harm, but there was little direct evidence.

Findings: From 11 295 literature citations associated with 10 PICO questions, 20 relevant studies were identified. An updated search identified 2 additional studies, for a total of 22 included studies (3 systematic reviews, 19 primary studies), which were reviewed and synthesized. Based on this analysis, 14 recommendations and 4 statements of good practice were developed. Overall, the evidence base was limited. Only 1 strong recommendation was formulated: screening for Alzheimer-type dementia starting at age 40 years. Four recommendations (managing risk factors for cardiovascular disease and stroke prevention, screening for obesity, and evaluation for secondary causes of osteoporosis) agreed with existing guidance for individuals without Down syndrome. Two recommendations for diabetes screening recommend earlier initiation of screening and at shorter intervals given the high prevalence and earlier onset in adults with Down syndrome.

Conclusions and Relevance: These evidence-based clinical guidelines provide recommendations to support primary care of adults with Down syndrome. The lack of high-quality evidence limits the strength of the recommendations and highlights the need for additional research.

RevDate: 2020-10-17

Fan YG, Pang ZQ, Wu TY, et al (2020)

Vitamin D deficiency exacerbates Alzheimer-like pathologies by reducing antioxidant capacity.

Free radical biology & medicine pii:S0891-5849(20)31280-6 [Epub ahead of print].

Vitamin D (VD) deficiency is prevalent among aging people and Alzheimer's disease (AD) patients. However, the roles of VD deficiency in the pathology of AD remain largely unexplored. In this study, APP/PS1 mice were fed a VD-deficient diet for 13 weeks to evaluate the effects of VD deficiency on the learning and memory functions and the neuropathological characteristics of the mice. Our study revealed that VD deficiency accelerated cognitive impairment in the APP/PS1 mice. Mechanistic studies revealed that VD deficiency promoted glial activation and increased inflammatory factor secretion. Furthermore, VD deficiency increased the production and deposition of Aβ by elevating the expression levels of amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1). In addition, VD deficiency increased the phosphorylation of Tau at Thr181, Thr205 and Ser396 by increasing the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3α/β (GSK3α/β) and promoted synaptic dystrophy and neuronal loss. All these effects of VD deficiency may be ascribed to enhanced oxidative stress via the downregulation of superoxide dismutase 1 (SOD1), glutathione peroxidase 4 (GPx4) and cystine/glutamate exchanger (xCT). Taken together, our data suggest that VD deficiency exacerbates Alzheimer-like pathologies via promoting inflammatory stress, increasing Aβ production and elevating Tau phosphorylation by decreasing antioxidant capacity in the brains of APP/PS1 mice. Hence, rescuing the VD status of AD patients should be taken into consideration during the treatment of AD.

RevDate: 2020-10-19

Veenman L (2020)

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start.

International journal of molecular sciences, 21(20): pii:ijms21207586.

Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects-fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson's disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health-on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer's disease, raloxifene may not cure diagnosed Alzheimer's disease. However, the onset of Alzheimer's disease may be delayed or arrested by raloxifene's capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer's disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer's disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.

RevDate: 2020-10-16

Kargbo RB (2020)

Selective DYRK1A Inhibitor for the Treatment of Neurodegenerative Diseases: Alzheimer, Parkinson, Huntington, and Down Syndrome.

ACS medicinal chemistry letters, 11(10):1795-1796.

RevDate: 2020-10-16

d'Errico P, M Meyer-Luehmann (2020)

Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer's Disease.

Frontiers in aging neuroscience, 12:265.

Alzheimer's disease (AD) is pathologically defined by extracellular accumulation of amyloid-β (Aβ) peptides generated by the cleavage of amyloid precursor protein (APP), strings of hyperphosphorylated Tau proteins accumulating inside neurons known as neurofibrillary tangles (NFTs) and neuronal loss. The association between the two hallmarks and cognitive decline has been known since the beginning of the 20th century when the first description of the disease was carried out by Alois Alzheimer. Today, more than 40 million people worldwide are affected by AD that represents the most common cause of dementia and there is still no effective treatment available to cure the disease. In general, the aggregation of Aβ is considered an essential trigger in AD pathogenesis that gives rise to NFTs, neuronal dysfunction and dementia. During the process leading to AD, tau and Aβ first misfold and form aggregates in one brain region, from where they spread to interconnected areas of the brain thereby inducing its gradual morphological and functional deterioration. In this mini-review article, we present an overview of the current literature on the spreading mechanisms of Aβ and tau pathology in AD since a more profound understanding is necessary to design therapeutic approaches aimed at preventing or halting disease progression.

RevDate: 2020-10-16

Maresova P, Hruska J, Klimova B, et al (2020)

Activities of Daily Living and Associated Costs in the Most Widespread Neurodegenerative Diseases: A Systematic Review.

Clinical interventions in aging, 15:1841-1862 pii:264688.

Nowadays, the population is rapidly ageing because of increasing life expectancy and decreasing birth rates. Thus, the purpose of this systematic review is to prepare a comprehensive overview which identifies the activities of daily living (ADLs) that are gradually reduced among patients with dementia, as well as explore the therapies applied in relation to dementia and how they effectively improve the quality of life (QoL) of patients and caregivers. Furthermore, we aim to summarise the ADL activities influenced by therapies and examine the treatment costs and care for patients so that recommendations for research and development (R&D) can be made to improve both the QoL of people with dementia and cost-saving measures. The research focuses on four selected neurodegenerative diseases: Alzheimer, Parkinson, vascular dementia, and amyotrophic lateral sclerosis. Therefore, the peer-reviewed English written articles from 2014 to 2019 were searched between September 1 and December 13, 2019. Twenty-seven papers were included in the analysis. The results show that essential assistance occurs in connection with activities: eating, drinking, dressing, bathing, personal hygiene, use of the toilet, and transport. By contrast, shopping or cleaning is not addressed as much. A lower ability to take care of oneself is connected with poor patient health and higher social care costs because the patient requires care from external sources, such as home aid or nurse visits. The challenge that remains is to shift new knowledge from scientific disciplines and connect it with the needs of patients to remove legitimate barriers and increase the acceptance of new solutions by popularisation. Additionally, regarding the burden on caregivers, it would be appropriate to promote this area of education and employment so that family members can use formal caregivers, ensuring them free time and much-needed rest.

RevDate: 2020-10-13

Tran AT, Pham TB, Kim JY, et al (2020)

Alzheimer's diagnosis using deep learning in segmenting and classifying 3D brain MR images.

The International journal of neuroscience [Epub ahead of print].

Dementia is one of the brain diseases with serious symptoms such as memory loss, and thinking problems. According to the World Alzheimer Report 2016, in the world, there are 47 million people having dementia and it can be 131 million by 2050. There is no standard method to diagnose dementia, and consequently unable to access the treatment effectively. Hence, the computational diagnosis of the disease from brain Magnetic Resonance Image (MRI) scans plays an important role in supporting the early diagnosis. Alzheimer's Disease (AD), a common type of Dementia, includes problems related to disorientation, mood swings, not managing self-care, and behavioral issues. In this article, a new computational method is presented to diagnose AD from 3D brain MRI. The efficient approach comprises two phases: I) segmentation and II) classification, both based on deep learning. After the brain tissues are segmented by a model that used Gaussian Mixture Model (GMM) as an additional input for Convolutional Neural Network (CNN), a new model for combining Extreme Gradient Boosting (XGBoost) and Support Vector Machine (SVM) is used to classify Alzheimer's disease based on the segmented tissues. For comparison, the new method was evaluated using the AD-86 and AD-126 datasets leading to Dice 0.96 for segmentation in both datasets and accuracies 0.88, and 0.80 for classification, respectively.

RevDate: 2020-10-13

Kim D, Yoon HE, Park HS, et al (2020)

Development of donepezil-induced hypokalemia following treatment of cognitive impairment.

Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer's disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.

RevDate: 2020-10-12

Insel PS, Hansson O, N Mattsson-Carlgren (2020)

Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment.

JAMA neurology pii:2771412 [Epub ahead of print].

Importance: Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E ε4 (APOE ε4) in Alzheimer disease and the ease of identifying ε4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation.

Objective: To determine whether the ε2 allele is protective against Aβ accumulation in the presence of the ε4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction.

This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded.

Main Outcomes and Measures: Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite.

Results: A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE ε2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ε24, 1.11 [95% CI, 1.08-1.14]; ε34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of ε4, with Aβ levels in the APOE ε24 group (n = 115; ε24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ε34 group (n = 1295; 0.012 SUVR increase per year of age; P = .04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ε4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ε4 carriers and noncarriers = -0.084, P = .005; after adjusting for 18F-florbetapir = -0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P = .78).

Conclusions and Relevance: These findings suggest that the protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the ε2 allele in order to facilitate Aβ clearance in ε4 carriers. Such a treatment strategy is appealing, as ε4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ε4 carriers begin to accumulate Aβ in early middle age.

RevDate: 2020-10-08

Adeowo FY, Ejalonibu MA, Elrashedy AA, et al (2020)

Multi-target approach for Alzheimer's disease treatment: computational biomolecular modeling of cholinesterase enzymes with a novel 4-N-phenylaminoquinoline derivative reveal promising potentials.

Journal of biomolecular structure & dynamics [Epub ahead of print].

The identification of dual inhibitors targeting the active sites of the cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), have lately surfaced as a multi-approach towards Alzheimer treatment. More recently, a novel series of 4-N-phenylaminoquinolines was synthesized and evaluated against AChE and BuChE in which one of the compounds displayed appreciable inhibition compared to the standard compound, galantamine. To provide a clearer picture of the inhibition mechanism of this potent compound at the molecular level, computational biomolecular modeling was carried out. The investigation was initiated with the exploration of the chemical properties of the identified compound 11 b and reference drug, galantamine. Density functional theory (DFT) calculations reveal some conceptual parameters that provide information on the stability and reactivity of the compounds as potential inhibitors. To unveil the binding mechanism, energetics and enzyme-ligand interactions, molecular dynamics (MD) simulations of six different systems were executed over a period. Calculated binding free energy values are in the same order with experimental IC50 data. Identification of the main residues driving optimum binding of the active compound 11 b to the binding region of both AChE and BuChE showed Trp81 and Trp110 as the most important, respectively. It was proposed that the studied compound could serve as a dual inhibitor for AChE and BuChE, therefore, would potentially be a promising moiety in a multi-target approach for the treatment of Alzheimer's disorder. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-10-07

Lin G, Ji K, Li S, et al (2020)

The Genetics Analysis of Molecular Pathogenesis for Alzheimer's Disease.

European neurology pii:000509799 [Epub ahead of print].

INTRODUCTION: The molecular pathogenesis of Alzheimer's disease (AD) is still not clear, and the relationship between gene expression profile for different brain regions has not been studied.

OBJECTIVE: Bioinformatic analysis at the genetic level has become the best way for the pathogenesis research of AD, which can analyze the abovementioned relationship.

METHODS: In this study, the datasets of AD were obtained from the Gene Expression Omnibus (GEO), and Qlucore Omics Explorer (QOE) software was used to screen differentially expressed genes of GSE36980 and GSE9770 and verify gene expression of GSE63060. The Gene Ontology (GO) function enrichment analysis of these selected genes was conducted by Database for Annotation, Visualization, and Integrated Discovery (DAVID), and then the gene/protein interaction network was established by STRING to find the related proteins. R language was used for drafting maps and plots.

RESULTS: There were 20 differentially expressed genes related to AD selected from GSE36980 (p = 6.2e-6, q = 2.9422e-4) and GSE9770 (p = 3.3e-4, q = 0.016606). Their expression levels of the AD group were lower than those in the control group and varied among different brain regions. Cellular morphogenesis and establishment or maintenance of cell polarity were enriched, and LRRTM1 and RASAL1 were identified by the integration network. Moreover, the analysis of GSE63060 verified the expression level of LRRTM1 and RASAL1 in Alzheimer's patients, which was much lower than that in normal people aged >65 years.

CONCLUSIONS: The pathogenesis of AD at molecular levels may link to cell membrane structures and signal transduction; hence, a list of 20 genes, including LRRTM1 and RASAL1,potentially are important for the discovery of treatment target or molecular marker of AD.

RevDate: 2020-10-09

Zuo S, Yu J, Pan H, et al (2020)

Novel insights on targeting ferroptosis in cancer therapy.

Biomarker research, 8:50.

Ferroptosis belongs to a novel form of regulated cell death. It is characterized by iron dependence, destruction of intracellular redox balance and non-apoptosis. And cellular structure and molecules level changes also occur abnormally during ferroptosis. It has been proved that ferroptosis exist widespreadly in many diseases, such as heart disease, brain damage or alzheimer disease. At the same time, the role of ferroptosis in cancer cannot be underestimated. More and more indications have told that ferroptosis is becoming a powerful weapon against cancer. In addition, therapies rely on ferroptosis have been applied to the clinic. Therefore, it is necessary to understand this newly discovered form of cell death and its connection with cancer. This review summarizes the mechanism of ferroptosis, ferroptosis inducers based on different targets and inspection methods. At last, we analyzed the relationship between ferroptosis and malignancies, in order to provide a novel theory basis for cancer treatment.

RevDate: 2020-10-07

Visioli F, Rodríguez-Pérez M, Gómez-Torres Ó, et al (2020)

Hydroxytyrosol improves mitochondrial energetics of a cellular model of Alzheimer's disease.

Nutritional neuroscience [Epub ahead of print].

Mitochondrial energetic deficit is one of the hallmarks of neurodegenerative disorders, e.g. Alzheimer´s disease (AD). Adherence to a Mediterranean diet is associated with lower incidence of cognitive decline and AD and extra virgin olive oil's (poly)phenols such as oleuropein and hydroxytyrosol (HT) are being actively studied in this respect. In this study, we assessed the effects of HT on mitochondrial energetic dysfunction in the 7PA2 cells cellular model, i.e. one of the best cellular models of Aβ toxicity with a well-characterized mitochondrial dysfunction typically observed in AD. We report an increase of new mitochondria at 8 h post HT-treatment, which was followed by higher mitochondrial fusion. Further, ATP concentrations were significantly increased after 24 h of treatment with HT as compared with controls. Our data suggest that HT may revert the energetic deficit of a cellular model of AD by potentiating mitochondrial activity. Because HT is being proposed as dietary supplement or component of functional foods, future studies in appropriate animal models and - eventually - humans are warranted to further investigate its potential neuroprotective actions in AD.

RevDate: 2020-10-07

Roda AR, Esquerda-Canals G, Martí-Clúa J, et al (2020)

Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer's Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation.

Pharmaceutics, 12(10): pii:pharmaceutics12100944.

Clinical symptoms of Alzheimer's Disease (AD) include behavioral alterations and cognitive impairment. These functional phenotypes early occur in triple-transgenic (3xTg-AD) mice. Specifically, behavioral alterations are first detected when mice are at around 2.5 months old and cognitive impairment in between 3- and 5-month-old mice. In this work, the effect of chronic Aβ-immunotherapy on behavioral and cognitive abilities was tested by monthly administering the antibody fragment scFv-h3D6 to 3xTg-AD female mice from 5 to 9 months of age. An untreated group was used as a reference, as well as to attain some information on the effect of training during the longitudinal study. Behavioral and psychological symptoms of dementia (BPSD)-like symptoms were already evident in 5-month-old mice, in the form of neophobia and anxious-like behavior. The exploratory activity decreased over the longitudinal study, not only for 3xTgAD mice but also for the corresponding non-transgenic mice (NTg). Learning abilities of 3xTg-AD mice were not seriously compromised but an impairment in long-term spatial memory was evident at 5 months of age. Interestingly, scFv-h3D6-treatment affected the cognitive impairment displayed by 5-month-old 3xTg-AD mice. It is worth noting that training also reduced cognitive impairment of 3xTg-AD mice over the longitudinal study, suggesting that to properly quantify the isolated therapeutic potential of any drug on cognition using this model it is convenient to perform a prompt, age-matched study rather than a longitudinal study. In addition, a combination of both training and Aβ-immunotherapy could constitute a possible approach to treat Alzheimer's disease.

RevDate: 2020-10-06

Potshangbam AM, Nandeibam A, Amom T, et al (2020)

An in silico approach to identify potential medicinal plants for treating Alzheimer disease: a case study with acetylcholinesterase.

Journal of biomolecular structure & dynamics [Epub ahead of print].

Alzheimer's disease (AD) is a progressive neurological disorder affecting an estimated 10 million people worldwide. There is no cure for AD, and only a handful of drugs are known to provide some relief of the symptoms. The prescription drug donepezil has been widely used to treat to slow the progression and onset of the disease; however, the unpleasant side effects have paved the way to find alternative medicines. Many herbs are known to improve brain function, but evidence of medicinal plants that can treat AD is limited due to the lack of concrete rational evidences. Moreover, the traditional method of randomly screening plant extract against AD targets takes time and resources. In this study, a receptor-based in silico method has been implemented which serves to accelerate the process of identification of medicinal plants useful for treatment of AD. A database of natural compounds was compiled to identify hits against acetylcholinesterase (AChE). Receptor-based pharmacophore screening was performed, and selected hits were subjected to docking and molecular dynamics simulations. Molecular Mechanics/Generalized Born surface area (MM/GBSA) calculations were carried out to identify the best scoring hits further. In vitro assays were done for the plant extracts containing the top-scoring hits against AChE. Three plant extracts showed favorable inhibitory activity. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-10-06

Hsieh WT, Lefort-Besnard J, Yang HC, et al (2020)

Behavior Score-Embedded Brain Encoder Network for Improved Classification of Alzheimer Disease Using Resting State fMRI.

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference, 2020:5486-5489.

The ability to accurately detect onset of dementia is important in the treatment of the disease. Clinically, the diagnosis of Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI) patients are based on an integrated assessment of psychological tests and brain imaging such as positron emission tomography (PET) and anatomical magnetic resonance imaging (MRI). In this work using two different datasets, we propose a behavior score-embedded encoder network (BSEN) that integrates regularly adminstrated psychological tests information into the encoding procedure of representing subject's resting-state fMRI data for automatic classification tasks. BSEN is based on a 3D convolutional autoencoder structure with contrastive loss jointly optimized using behavior scores from Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Our proposed classification framework of using BSEN achieved an overall recognition accuracy of 59.44% (3-class classification: AD, MCI and Healthy Control), and we further extracted the most discriminative regions between healthy control (HC) and AD patients.

RevDate: 2020-10-04

Cleveland ML (2020)

Preserving Cognition, Preventing Dementia.

Clinics in geriatric medicine, 36(4):585-599.

Dementia incidence continues to rise in the United States and around the world. Although age is the single biggest risk factor for the development of dementia, it is not considered normal sequelae of aging. Although there has been little to no progress made in the past couple of decades in the treatment or cure of Alzheimer disease, there has been significant progress made in prevention. Single factors, such as hearing loss or cardiovascular risk factors, may increase the risk for cognitive decline. The opportunity to mitigate these risk factors provides an exciting new healthy aging approach to dementia prevention.

RevDate: 2020-10-05

Ewelina B, Julie M, FM Teresa (2020)

Gender medicine: Towards a gender-specific treatment of neuropsychiatric disorders.

Handbook of clinical neurology, 175:437-448.

Sex and gender are increasingly recognized as major influencing factors in disorders across all medical specialties. Even though there is ample evidence of sex and gender differences in neuropsychiatric disorders, a sex and gender-differentiated approach has not yet been sufficiently applied to diagnostics and management. Therefore, there is an urgent need to establish general recommendations and guidelines toward precision and sex/gender medicine, with regard to dosage, tolerability, interactions and side effects, sensitivity of diagnostic tests, and distinct treatment strategies. This chapter illustrates the current knowledge about sex and gender aspects in neuropsychiatric disorders, providing a base not only to assist the clinician in the handling of specific pathologic entities, but also to sensitize medical practitioners to consider sex and gender in clinical decision-making. As such, the chapter is a call to action to physicians and researchers to produce more sex- and gender-stratified evidence, leading to an acceleration of guideline development. Such novel guidelines will provide a base for medical education, of both medical students and specialists, as well as a reference point for practitioners, toward precision medicine.

RevDate: 2020-10-04

Dalakas MC, Alexopoulos H, PJ Spaeth (2020)

Complement in neurological disorders and emerging complement-targeted therapeutics.

Nature reviews. Neurology [Epub ahead of print].

The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I-III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies.

RevDate: 2020-10-02

Wang X, Li Z, Li C, et al (2020)

Electroacupuncture with Bushen Jiannao improves cognitive deficits in senescence-accelerated mouse prone 8 mice by inhibiting neuroinflammation.

Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan, 40(5):812-819.

OBJECTIVE: To investigate effect of electroacupuncture (EA) with Bushen Jiannao on learning and memory ability in senescence-accelerated mouse prone 8 (SAMP8) mice and the related mechanisms.

METHODS: 8-month-old senescence-accelerated-resistant (SAMR1) and SAMP8 mice were treated with EA at Baihui (GV 20), Shenshu (BL 23), and Taixi (KI 3) acupoint once a week for 8 weeks. The Morris water maze, enzyme linked immunosorbent assay, immunohistochemistry, and Western blot were used to assess Alzheimer's disease (AD)-associated cognitive and neuroinflammatory phenotypes.

RESULTS: Our data showed that EA treatment decreased activation of microglia and astrocytes, decreased levels of inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-17, and improved spatial memory deficits in SAMP8 mice. EA therapy with Bushen Jiannao exhibited anti-inflammatory properties and improved cognitive function.

CONCLUSION: The present study indicates that EA treatment based on the interaction between kidney and brain can improve learning and memory ability by inhibiting activation of astrocytes and microglia and decreasing expression of pro-inflammatory cytokines, TNF-α and IL-17. EA treatment based on the interaction between kidney and brain may be an effective treatment for AD.

RevDate: 2020-10-07

Goudarzi G, Hamidabadi HG, Bojnordi MN, et al (2020)

Role of cerebrospinal fluid in differentiation of human dental pulp stem cells into neuron-like cells.

Anatomy & cell biology, 53(3):292-300.

Human dental pulp stem cells (hDPSCs) could be differentiated into neuron like-cells under particular microenvironments. It has been reported that a wide range of factors, presented in cerebrospinal fluid (CSF), playing part in neuronal differentiation during embryonic stages, we herein introduce a novel culture media complex to differentiate hDPSCs into neuron-like cells. The hDPSCs were initially isolated and characterized. The CSF was prepared from the Cisterna magna of 19-day-old Wistar rat embryos, embryonic cerebrospinal fluid (E-CSF). The hDPSCs were treated by 5% E-CSF for 2 days, then neurospheres were cultured in DMEM/F12 supplemented with 10-6 μm retinoic acid (RA), glial-derived neurotrophic factor and brain-derived neurotrophic factor for 6 days. The cells which were cultured in basic culture medium were considered as control group. Morphology of differentiated cells as well as process elongation were examined by an inverted microscope. In addition, the neural differentiation markers (Nestin and MAP2) were studied employing immunocytochemistry. Neuronal-like processes appeared 8 days after treatment. Neural progenitor marker (Nestin) and a mature neural marker (MAP2) were expressed in treated group. Moreover Nissl bodies were found in the cytoplasm of treated group. Taking these together, we have designed a simple protocol for generating neuron-like cells using CSF from the hDPSCs, applicable for cell therapy in several neurodegenerative disorders including Alzheimer's disease.

RevDate: 2020-10-01

Marí M, de Gregorio E, de Dios C, et al (2020)

Mitochondrial Glutathione: Recent Insights and Role in Disease.

Antioxidants (Basel, Switzerland), 9(10): pii:antiox9100909.

Mitochondria are the main source of reactive oxygen species (ROS), most of them deriving from the mitochondrial respiratory chain. Among the numerous enzymatic and non-enzymatic antioxidant systems present in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for maintaining the appropriate mitochondrial redox environment. mGSH's ability to act directly or as a co-factor in reactions catalyzed by other mitochondrial enzymes makes its presence essential to avoid or to repair oxidative modifications that can lead to mitochondrial dysfunction and subsequently to cell death. Since mitochondrial redox disorders play a central part in many diseases, harboring optimal levels of mGSH is vitally important. In this review, we will highlight the participation of mGSH as a contributor to disease progression in pathologies as diverse as Alzheimer's disease, alcoholic and non-alcoholic steatohepatitis, or diabetic nephropathy. Furthermore, the involvement of mitochondrial ROS in the signaling of new prescribed drugs and in other pathologies (or in other unmet medical needs, such as gender differences or coronavirus disease of 2019 (COVID-19) treatment) is still being revealed; guaranteeing that research on mGSH will be an interesting topic for years to come.

RevDate: 2020-09-25

Abdel-Haq H (2020)

The Potential of Liquid Biopsy of the Brain Using Blood Extracellular Vesicles: The First Step Toward Effective Neuroprotection Against Neurodegenerative Diseases.

Molecular diagnosis & therapy pii:10.1007/s40291-020-00493-4 [Epub ahead of print].

Early diagnosis and biomarker-based ante-mortem tests are essential in efforts against the development of neurodegenerative diseases and can be considered primary neuroprotective measures. Blood is the ideal biofluid for a routine ante-mortem screening test. However, biomarker discovery in the blood is particularly difficult because of interference from factors both intrinsic and extrinsic to blood with the detection of hallmark neurodegenerative biomarkers, such as the pathological prion protein, amyloid-β, and others. Blood extracellular vesicles (EVs), such as exosomes, are cell-derived vesicles released into the blood from all parts of the body (including the brain and spinal cord). They are an enriched source of neural-derived EVs containing neurodegenerative biomarkers that mirror (in the blood) the condition present in the brain. The feasibility of using, and the reliability of, neural-derived blood EVs (NDBEVs) as a method of diagnosing Alzheimer disease and other neurodegenerative diseases has been assessed in strong proof-of-concept studies. Results from these studies strongly suggest that NDBEVs might represent the right strategy for specific, reliable, and early diagnosis of neurodegenerative diseases. Based on these results, NDBEVs might enable the creation of an ante-mortem blood test (liquid biopsy of the brain) for neurodegenerative diseases. This would enormously accelerate the therapy of neurodegenerative diseases. This review highlights the powerful potential of liquid biopsy of the brain using NDBEVs for early diagnosis and treatment of neurodegenerative diseases, and the challenges and limitations related to the identification of clinically applicable EV (exosomal) biomarkers using blood are discussed.

RevDate: 2020-09-28

Rong X, Xiang L, Li Y, et al (2020)

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics.

Frontiers in aging neuroscience, 12:248.

Increasing evidence indicates Chronic Periodontitis (CP) is a comorbidity of Alzheimer's disease (AD), which is the most common form of age-related dementia, and for the latter, effective diagnostic and treatment strategies are lacking. Although inflammation is present in both diseases, the exact mechanisms and cross-links between CP and AD are poorly understood; and a direct association between the two has not been reported. This study aimed to identify a direct serum proteins link between AD and CP. Two-dimensional differential in-gel electrophoresis was employed to analyze serum samples from 12 CP patients and 12 age-matched controls. Furthermore, to determine the molecular link between CP and AD, neuroblastoma SK-N-SH APPwt cells were treated with 1 μg/ml of lipopolysaccharide from Porphyromonas gingivalis (P.g-LPS). Ten differentially expressed proteins were identified in CP patients. Among them, nine proteins were up-regulated, and one protein was down-regulated. Of the 10 differentially expressed proteins, five proteins were reportedly involved in the pathology of AD: Cofilin-2, Cathepsin B, Clusterin, Triosephosphate isomerase, and inter-alpha-trypsin inhibitor heavy chain H4 (ITI-H4). Western blotting indicated significantly higher expression of Cofilin-2, Cathepsin B, and Clusterin and lower expression of ITI-H4 in the CP group than in the Control group. The serum concentration of Cathepsin B has a good correlation with MMSE scores. Moreover, the protein level of Cathepsin B (but not that of ADAM10 and BACE1) increased significantly along with a prominent increase in Aβ1-40 and Aβ1-42 in the cell lysates of P.g-LPS-treated SK-N-SH APPwt cells. Cathepsin B inhibition resulted in a sharp decrease in Aβ1-40 and Aβ1-42 in the cell lysates. Furthermore, TNF-α was one of the most important inflammatory cytokines for the P.g-LPS-induced Cathepsin B upregulation in SK-N-SH APPwt cells. These results show that CP and AD share an association, while Cathepsin B could be a key link between the two diseases. The discovery of the identical serum proteins provides a potential mechanism underlying the increased risk of AD in CP patients, which could be critical for elucidating the pathophysiology of AD.

RevDate: 2020-09-24

Sun K, Jing X, Guo J, et al (2020)

Mitophagy in degenerative joint diseases.

Autophagy [Epub ahead of print].

Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the maintenance of mitochondria homeostasis and function is important. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, functions to maintain mitochondrial quality control and homeostasis. IVDD and OA are similar joint diseases involving the degradation of cartilaginous tissues that are mainly caused by oxidative stress, cell apoptosis and extracellular matrix (ECM) degradation. Over the past decade, accumulating evidence indicates the essential role of mitophagy in the pathogenesis of IVDD and OA. Importantly, strategies by the regulation of mitophagy exert beneficial effects in the pre-clinical experiments. Given the importance and novelty of mitophagy, we provide an overview of mitophagy pathways and discuss the roles of mitophagy in IVDD and OA. We also highlight the potential of targeting mitophagy for the treatment of degenerative joint diseases. Abbreviations: AD: Alzheimer disease; AF: annulus fibrosus; ADORA2A/A2AR: adenosine A2a receptor; AMBRA1: autophagy and beclin 1 regulator 1; BMSCs: bone marrow mesenchymal stem cells; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CDH6: cadherin 6; CEP: cartilaginous endplates; circRNA: circular RNA; DNM1L/DRP1: dynamin 1-like; ECM: extracellular matrix; HIF1A: hypoxia inducible factor 1: alpha subunit; IL1B: interleukin 1 beta; IMM: inner mitochondrial membranes; IVDD: intervertebral disc degeneration; MAPK8/JNK: mitogen-activated protein kinase 8; MFN1: mitofusin 1; MFN2: mitofusin 2; MIA: monosodium iodoacetate; RHOT/MIRO: ras homolog family member T; MMP: mitochondrial transmembrane potential; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NFE2L2: nuclear factor: erythroid 2 like 2; NP: nucleus pulposus; OA: osteoarthritis; OPA1: OPA1: mitochondrial dynamin like GTPase; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PD: Parkinson disease; PGAM5: PGAM family member 5; PPARGC1A/PGC-1A: peroxisome proliferator activated receptor: gamma: coactivator 1 alpha; PHF23: PHD finger protein 23; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SfMSCs: synovial fluid MSCs; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SIRT3: sirtuin 3; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; Ub: ubiquitin; UBL: ubiquitin-like; VDAC: voltage-dependent anion channel.

RevDate: 2020-09-22

Ibrahim MA, Haleem M, AbdelWahab SA, et al (2020)

Sildenafil ameliorates Alzheimer disease via the modulation of vascular endothelial growth factor and vascular cell adhesion molecule-1 in rats.

Human & experimental toxicology [Epub ahead of print].

Alzheimer disease (AD) is a chronic neurodegenerative disease with multi-pathways pathogenesis. Sildenafil is a selective phosphodiesterase-5 inhibitor with a potential benefit in the treatment of AD. This study investigated the possible mechanisms underlying the effect of sildenafil in AD with emphasis on vascular endothelial growth factor (VEGF), and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four adult male rats were classified into four groups; control group: received vehicles, sildenafil-control: received sildenafil (15 mg/kg/day, p.o.), AD group received Aluminum (25 mg/kg/day, p.o.), AD-treated group: received sildenafil (15 mg/kg/day, p.o.) for 6 weeks. AD was assessed by memory performance test and confirmed by histopathological examination and immunostaining of, neurogenesis marker nestin and α-synuclein. The levels of VEGF-A, VCAM-1, oxidative stress markers and TNF-α in brain tissue were evaluated. AD rats showed histopathological evidences of AD; along with increased latency time in the memory test. There was a decrease in VEGF-A, and an increase in VCAM-1, TNF-α, and oxidative stress markers. Immunohistochemical study showed a significant increase in α-synuclein and a significant decrease in nestin expressions in brain tissues. Sildenafil administration ameliorated the histopathological changes and decreased latency time. Such effect was associated with a decrease in VCAM-1, TNF-α and oxidative stress as well as an increase in VEGF-A. Sildenafil caused a significant increase in nestin and a decrease in α-synuclein immunostaining. These findings suggested a protective effect of sildenafil via modulation of VEGF-A, and VCAM-1.

RevDate: 2020-09-22

Wu B, Cai H, Tang S, et al (2020)

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics pii:10.1007/s13311-020-00930-6 [Epub ahead of print].

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.

RevDate: 2020-09-22

Mishra J, Kumar B, Pandey M, et al (2020)

Carbon Nano Tubes: Novel drug delivery system in amelioration of Alzheimer's disease.

Combinatorial chemistry & high throughput screening pii:CCHTS-EPUB-110064 [Epub ahead of print].

BACKGROUND: Alzheimer's disease is an irreversible, progressive brain disorder manifested with symptoms like loss of memory (known as dementia), personality changes, loss of cognition, impaired movement, confusion, deteriorated planning and thought process. Neurodegeneration in Alzheimer's disease is the result of deposition of protein beta-amyloid that forms plaques and another protein called tau, forming tangles that prevent proper functioning of nerve cells in the brain.

METHODS: The goal of the review was to comprehensively study the utilization of nanotechnology and the role that carbon nanotubes can play as a drug delivery system for amelioration of Alzheimer's disease.

RESULTS: Nanotechnology is one of the most researched domains of modern science. It contributes significantly to therapeutics by facilitating drug therapy to reach the target sites, which are otherwise difficult to reach with conventional drug delivery systems. Carbon nanotubes are the allotropes of carbon in which several carbon atoms bind with each other to form a cylindrical or a tube-like structure. The carbon nanotubes possess several unique qualities, which confers them with a high potential of being utilized as an efficient drug delivery system. They offer high drug loading, can readily cross the toughest biological barriers like BBB. Carbon nanotubes also facilitate the passage of drugs to the brain via the olfactory route, which further helps in restoring normal autophagy, thus preventing the elimination of autophagic chemicals. They can carry a vast range of cargos, including drugs, antigens, genetic materials, and biological macromolecules.

CONCLUSION: Carbon nanotubes are highly promising drug delivery system for anti-Alzheimer's drugs. They have potential of overcoming the various biological barriers like BBB. However, more extensive research is required so as to set up a firm base for development of advanced commercial products based on carbon nanotubes for treatment of Alzheimer's disease.

RevDate: 2020-10-01
CmpDate: 2020-09-30

Kainuma M, Funakoshi K, Ouma S, et al (2020)

The efficacy and safety of hachimijiogan for mild Alzheimer disease in an exploratory, open standard treatment controlled, randomized allocation, multicenter trial: A study protocol.

Medicine, 99(38):e22370.

BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done.

METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021.

DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD.

TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018).

RevDate: 2020-09-21

Lorettu L, Carpita B, Nivoli A, et al (2020)

Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis.

Clinical neuropharmacology, 43(5):158-161.

Although lithium is widely used as a first-line treatment for mood disorders, its mood-stabilizing effects remain not fully understood. A growing body of data are stressing that lithium seems to show broader properties, including neuroprotective effects. Lithium's ability to inhibit glycogen synthase kinase 3β, an enzyme that participates in the phosphorylation of τ, a microtubule-associated protein, stimulated interest in its possible therapeutic role in Alzheimer disease and other neurodegenerative disorders. Preliminary data also support exploration of lithium's potential therapeutic role in multiple sclerosis, an autoimmune disorder that is associated with co-occurring mood disorders. Lithium is associated with teratogenic risks to the developing fetus; however, recently revised downward estimates of its teratogenic risk of causing fetal cardiac malformation suggest that its potential therapeutic benefit to both mothers with bipolar disorder and their offspring should be considered in at least some cases. A 43-year-old woman previously diagnosed with bipolar disorder and MS was treated with lithium and thyroid hormone supplementation as her sole medications during her pregnancy. The patient remained euthymic throughout her pregnancy and over the course of her 5-year follow-up evaluations on this medication regimen. In addition to her stable mood, there has been no symptomatic progression or relapse of her MS, and her daughter continues to develop normally.The case supports consideration of balancing lithium's mood-stabilizing benefit with its known teratogenic risk during pregnancy. The case also supports exploration of possible additional benefit in the context of MS co-occurring with bipolar disorder.

RevDate: 2020-10-11

Vaz M, S Silvestre (2020)

Alzheimer's disease: Recent treatment strategies.

European journal of pharmacology, 887:173554 pii:S0014-2999(20)30646-4 [Epub ahead of print].

Alzheimer Disease (AD) is a neurodegenerative disease characterized by two neuropathological hallmarks: extracellular deposition of amyloid plaques and intracellular neurofibrillary tangles. Current treatment for AD (donepezil, galantamine, rivastigmine and memantine) is only symptomatic and has modest benefits. Thus, the development of drugs with the potential to change the progression of the disease has been a priority. Therapies targeting amyloid β have been the focus for almost 30 years. However, highly promising drugs recently failed to show clinical benefits in phase III trials. Even the positive findings presented by Biogen on Aducanumab are not entirely clear and further data is necessary to confirm its validity. Therefore, researchers are turning their efforts around to tau-targeting therapies, since tau protein appears to be better correlated with the severity of cognitive decline than amyloid β. Currently, most anti-tau agents in clinical trials are immunotherapies and they are in the early stages of clinical research. Four monoclonal antibodies anti-tau (Gosuranemab, Tilavonemab, Semorinemab and Zagotenemab) and one anti-tau vaccine (AADvac1) have reached phase II, so far. In this review, we discuss the potential disease-modifying agents tested in clinical trials and update the information of drugs that are still under clinical evaluation.

RevDate: 2020-09-17

Ballard C, Aarsland D, Cummings J, et al (2020)

Drug repositioning and repurposing for Alzheimer disease.

Nature reviews. Neurology pii:10.1038/s41582-020-0397-4 [Epub ahead of print].

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.

RevDate: 2020-09-16

Semenov VE, Zueva IV, Mukhamedyarov MA, et al (2020)

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease.

Molecules (Basel, Switzerland), 25(18): pii:molecules25184191.

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.

RevDate: 2020-10-05

Elzoghby AO, Abdelmoneem MA, Hassanin IA, et al (2020)

Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand.

Biomaterials, 263:120355 pii:S0142-9612(20)30601-3 [Epub ahead of print].

Recent progress in protein-based nanomedicine, inspired by the success of Abraxane® albumin-paclitaxel nanoparticles, have resulted in novel therapeutics used for treatment of challenging diseases like cancer and viral infections. However, absence of specific drug targeting, poor pharmacokinetics, premature drug release, and off-target toxicity are still formidable challenges in the clinic. Therefore, alternative protein-based nanomedicines were developed to overcome those challenges. In this regard, lactoferrin (Lf), a glycoprotein of transferrin family, offers a promising biodegradable well tolerated material that could be exploited both as an active therapeutic and drug nanocarrier. This review highlights the major pharmacological actions of Lf including anti-cancer, antiviral, and immunomodulatory actions. Delivery technologies of Lf to improve its pries and enhance its efficacy were also reviewed. Moreover, different nano-engineering strategies used for fabrication of drug-loaded Lf nanocarriers were discussed. In addition, the use of Lf for functionalization of drug nanocarriers with emphasis on tumor-targeted drug delivery was illustrated. Besides its wide application in oncology nano-therapeutics, we discussed the recent advances of Lf-based nanocarriers as efficient platforms for delivery of anti-parkinsonian, anti-Alzheimer, anti-viral drugs, immunomodulatory and bone engineering applications.

RevDate: 2020-09-15

Roda AR, Montoliu-Gaya L, Serra-Mir G, et al (2020)

Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice.

International journal of molecular sciences, 21(18): pii:ijms21186630.

Alzheimer's disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice.

RevDate: 2020-10-01
CmpDate: 2020-09-30

Wang M, Peng H, Peng Z, et al (2020)

Efficacy and safety of ginkgo preparation in patients with vascular dementia: A protocol for systematic review and meta-analysis.

Medicine, 99(37):e22209.

BACKGROUND: Vascular dementia has become the second most common type of dementia after Alzheimer disease. At present, there is no uniform standard for VaD treatment guidelines among countries. The efficacy of ginkgo biloba in the treatment of vascular dementia is still controversial. The purpose of this study is to evaluate the effectiveness and safety of ginkgo biloba in the treatment of vascular dementia through meta-analysis.

METHODS: Six English databases (PubMed, Web of science, Medline, EBASE, Springer Cochrane Library, and WHO International Clinical Trials Registry Platform) and 4 Chinese databases (Wan fang Database, Chinese Scientific Journal Database, China National Knowledge Infrastructure Database(CNKI) and Chinese Biomedical Literature Database) will be searched normatively according to the rule of each database from the inception to August 1, 2020. Two reviewers will independently conduct article selection, data collection, and risk of bias evaluation. Any disagreement will be resolved by discussion with the third reviewer. Either the fixed-effects or random-effects model will be used for data synthesis based on the heterogeneity test. The change in the scores on mini-mental state examination, activity of daily living scale and Montreal cognitive assement will be used as the main outcome measure, Hamilton depression scale, Hastgawa dementia scale, blessed dementia scale, clinical dmentia rating scale as the secondary outcome. Treatment emergent symptom scale, general physical examination (temperature, pulse, respiration, blood pressure), Routine examination of blood, urine and stool, electrocardiogram, liver and kidney function examination as the security indexs. RevMan5.3.5 will be used for meta-analysis.

RESULTS: This study will provide high-quality evidence to assess the effectiveness and safety of ginkgo preparation for vascular dementia.

CONCLUSION: This systematic review will explore whether ginkgo preparation is an effective and safe intervention for vascular dementia.

ETHICS AND DISSEMINATION: Ethical approval are not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and will be shared on social media platforms. This review will be disseminated in a peer-reviewed journal or conference presentation.

PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020167851.

RevDate: 2020-10-01
CmpDate: 2020-09-30

Wang H, Yu H, Song K, et al (2020)

Traditional Chinese medicine for mild cognitive impairment: A protocol for systematic review and network meta-analysis.

Medicine, 99(37):e22187.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer disease, which is the most common form of dementia in the world. In clinical practice, traditional Chinese medicine (TCM) interventions have been administered for MCI, However, there is still uncertain about what strategy of TCM interventions treatment should be preferred in clinical practice. This study aims to evaluate the efficacy and acceptability of different TCM therapies through systematic review and network meta-analysis.

METHODS: According to the strategy, the authors will retrieve a total of 7 electronic databases by August 2020, including PubMed, the Cochrane Library, EMbase, China National Knowledge Infrastructure, China Biological Medicine, Chongqing VIP, and Wan-fang databases. After a series of screening, 2 researchers will use Aggregate Data Drug Information System and Stata software to analyze the data extracted from the randomized controlled trials of TCM therapies for MCI. The primary outcome of this study is the improvement of cognitive function and the secondary outcome is the activities of daily living, clinical efficacy, and adverse events, and the quality of the evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument.

RESULTS: This study will provide a reliable evidence for the selection of TCM therapies in the treatment of MCI.

CONCLUSION: This study will generate evidence for different TCM therapies for MCI and provide a decision-making reference for clinical research.

ETHICS AND DISSEMINATION: This study does not require ethical approval. The results will be disseminated through a peer-reviewed publication.

OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/JV9KG.

RevDate: 2020-09-14

Vecchierini MF, Kilic-Huck U, Quera-Salva MA, et al (2020)

Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS).

Revue neurologique pii:S0035-3787(20)30656-1 [Epub ahead of print].

The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.

RevDate: 2020-10-13

Elibol B, Beker M, Terzioglu-Usak S, et al (2020)

Thymoquinone administration ameliorates Alzheimer's disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta1-42 infused rat model.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 79:153324 pii:S0944-7113(20)30156-2 [Epub ahead of print].

BACKGROUND: Thymoquinone (TQ), a biologically active ingredient of Nigella sativa, has anti-inflammatory, anti-oxidative and neuroprotective properties. Therefore, it could be a good candidate in the recovery of Alzheimer`s disease (AD) pathology rather than current symptomatic reliefs.

PURPOSE: In the present study, we examined the molecular healing effects of TQ in amyloid beta 1-42 (Aβ1-42) peptide-infused AD rat hippocampus.

STUDY DESIGN: A micro-osmotic pump containing aggregated Aβ1-42 was cannulated into the hippocampus of adult female rats. After two weeks infusion, the dose of TQ (10 mg/kg or 20 mg/kg) was determined according to the HPLC results of cerebrospinal fluid and TQ was given to rats intragastrically for 15 days.

METHODS: The memory performance of rats was determined by Morris water maze test. Afterwards, the acetylcholinesterase (AChE) level were measured by ELISA. Histopathological examinations of hippocampal tissue were performed for cell survival by Nissl staining, for detection of amyloid plaque deposits by Congo red staining and for determination of degenerating neurons by Fluoro Jade C staining. MicroRNA/mRNA levels and protein expressions of AD-related genes and proteins were analyzed by Real-Time Polymerase Chain Reaction and Western Blotting, respectively.

RESULTS: Administration of TQ enhanced the memory performance of Aβ1-42 infused rats and it also ameliorated the neuronal loss in the cornu ammonis (CA1), but not in the dentate gyrus (DG). In addition, TQ treatment decreased the fibril deposition whose accumulation was significantly higher in the Aβ1-42-infused animals compared to that of the control group. The expression profiles of mir29c and Bax which significantly upregulated in the Aβ1-42-infused animals were attenuated by TQ. Furthermore, administration of TQ decreased the expressions of Aβ, phosphorylated-tau, and BACE-1 proteins. There was no significant therapeutic effect of TQ on the AKT/GSK3β or MAPK signaling pathways which were affected due to Aβ1-42 infusion.

CONCLUSION: TQ has the capacity to recover the neuropathology by removing Aβ plaques and by restoring neuron viability. All might have established the molecular basement of the consolidation in the memory observed by means of TQ treatment.

RevDate: 2020-10-01
CmpDate: 2020-09-28

Flores J, Noël A, Foveau B, et al (2020)

Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.

Nature communications, 11(1):4571.

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.

RevDate: 2020-09-11

Guo J, Wang Z, Liu R, et al (2020)

Memantine, Donepezil, or Combination Therapy-What is the best therapy for Alzheimer's Disease? A Network Meta-Analysis.

Brain and behavior [Epub ahead of print].

INTRODUCTION: Alzheimer's disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple treatment comparison meta-analysis assessed the efficacy of these regimens and placebo in the management of AD.

METHODS: We searched PubMed, Embase, the Cochrane Library, and Wanfang Med Online and China National Knowledge Infrastructure for English and Chinese publications from the first records to 17 April 2020. Two investigators scanned articles for placebo-controlled trials of memantine and donepezil alone and in combination. We extracted data on the following outcomes: cognition, global assessment, daily activities, neuropsychiatric symptoms, adverse events, and the acceptability and cost of these treatment regimens.

RESULTS: Of 936 records screened, we included 54 trials in this analysis. The combination therapy was more effective in improving cognition (mean difference (MD)-5.01, 95% credible interval (95% Crl) -10.73 to 0.86 in the Alzheimer's Disease Assessment Scale-Cognitive Subscale; MD 9.61, 95% Crl 2.29 to 16.97 in the Severe Impairment Battery), global assessment (MD -2.88, 95% Crl -6.04 to 0.40), daily activities (MD 13.06, 95% Crl -34.04 to 58.92), and neuropsychiatric symptoms (MD -6.84, 95% Crl -10.62 to -2.82) compared with placebo. Memantine was more acceptable than placebo (MD 0.93, 95% Crl 0.69 to 1.22).

CONCLUSIONS: Memantine plus donepezil showed superior outcomes for cognition, global assessment, daily activities, and neuropsychiatric symptoms, but lower acceptability than monotherapy and placebo. Combination therapy may be more cost-effective, because memantine slows the progression of AD.

RevDate: 2020-09-11

Stazi M, O Wirths (2020)

Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer's Disease.

Molecular neurobiology pii:10.1007/s12035-020-02120-z [Epub ahead of print].

Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer's disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.

RevDate: 2020-09-11

Cirrito JR, Wallace CE, Yan P, et al (2020)

Effect of Escitalopram on Aβ levels and plaque load in an Alzheimer mouse model.

Neurology pii:WNL.0000000000010733 [Epub ahead of print].

RATIONALE: Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into amyloid-β (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter , SERT, would suppress Aβ levels in mice.

OBJECTIVES: We hypothesized that acute treatment with ESC would reduce Aβ generation which would be reflected chronically with a significant reduction in Aβ plaque load.

METHODS: We performed in vivo microdialysis and in vivo two-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/PS1 mouse model of Alzheimer's disease treated with vehicle or ESC. We also chronically treated mice with ESC to determine the effect on plaques histologically.

RESULTS: ESC acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of ESC significantly reduced plaque load by 28% and 34% at 2.5 mg/day and 5 mg/day, respectively. ESC at 5mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.

CONCLUSIONS: ESC significantly reduced Aβ in mice similar to previous findings in humans treated with acute dosing of an SSRI.

RevDate: 2020-09-28

Chai X, Zhang W, Li L, et al (2020)

Profile of MIF in Developing Hippocampus: Association With Cell Proliferation and Neurite Outgrowth.

Frontiers in molecular neuroscience, 13:147.

Proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and has been found involved in many neurological diseases such as Alzheimer disease (AD), epilepsy, and multiple sclerosis. Previous studies have shown that MIF is expressed in neocortex, hippocampus, hypothalamus, cerebellum, and spinal cord in adult mice. It is expressed by astrocytes and activates microglias in neuroinflammation. Further studies have shown that MIF is detected in moss fibers of dentate granule cells and in apical dendrites of pyramidal neurons in adult hippocampus. Only NeuroD-positive immature granule neurons but not NeuN-positive mature neurons express MIF. These findings led us eager to know the exact role of MIF in the development of hippocampus. Therefore, we systematically checked the spatial and temporal expression pattern of MIF and characterized MIF-positive cells in hippocampus from mice aged from postnatal day 0 (P0) to 3 months. Our results showed that the lowest level of MIF protein occurred at P7 and mif mRNA increased from P0, reached a peak at P7, and stably expressed until P30 before declining dramatically at 3 months. MIF was localized in fibers of GFAP- and BLBP-positive radial glial precursor cells in dentate gyrus (DG). DCX-expressing newly generated neurons were MIF-negative. Inhibition of MIF by MIF antagonist S, R-3-(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) reduced BrdU-positive cells. Interestingly, MIF was expressed by NeuN-positive GABAergic interneurons including parvalbumin-and Reelin-expressing cells in the DG. Neither NeuN-positive granule cells nor NeuN-positive pyramidal neurons expressed MIF. In transgenic mice, POMC-EGFP-positive immature dentate granule cells and Thy1-EGFP-positive mature granule cells were MIF-negative. Treatment of neuronal cultures with ISO-1 inhibited neurite outgrowth. Therefore, we conclude that MIF might be important for feature maintenance of neural stem cells and neurite outgrowth during hippocampal development.

RevDate: 2020-09-29
CmpDate: 2020-09-29

Zhao L, Li Z, Vong JSL, et al (2020)

Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain.

Nature communications, 11(1):4413.

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.

RevDate: 2020-09-05

Binda A, Murano C, I Rivolta (2020)

Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer's Disease: A State-of-the-Art (2017-2020).

International journal of nanomedicine, 15:6113-6135.

The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer's disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017-2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.

RevDate: 2020-09-15

Perera G, Mueller C, R Stewart (2020)

Factors associated with slow progression of cognitive impairment following first dementia diagnosis.

International journal of geriatric psychiatry [Epub ahead of print].

OBJECTIVES: To investigate the extent to which slow progression of dementia after diagnosis might be predicted from routine longitudinal healthcare data, in order to clarify characteristics of people who experience this outcome.

METHODS: A retrospective observational study was conducted using data from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre Case Register. This study included all patients receiving a first dementia diagnosis between 2006 and 2017, restricted to those with a baseline Mini-Mental State Examination (MMSE) score within 6 months of initial diagnosis of dementia and at least one MMSE score after 3 years post-diagnosis. Slow progression was defined as a change in MMSE score of -1, 0 or an increase at the follow-up point. This group was compared to the remainder with an MMSE decline of -2 or more.

RESULTS: Overall, 682 patients with slow progression were compared to 1045 with faster progression. In the confounder-adjusted multivariate logistic regression model, slow progression was more likely in younger patients (age 65-74 years; odds ratio: 1.18; 95% confidence intervals: 1.04-1.37), males (1.24; 1.01-1.53), those with moderate or severe dementia according to MMSE, patients with mixed-type dementia (2.06; 1.11-3.82) compared to Alzheimer's disease and less likely in those receiving acetylcholinesterase inhibitor (AChEI) treatment (0.57; 0.46-0.71).

CONCLUSION: Slow dementia progression after diagnosis was common in patients with mixed Alzheimer's and vascular dementia, younger age, males and non-receipt of AChEIs, possibly suggesting non-Alzheimer pathologies and clarifying such predictors is important, as there is currently very limited information on which to base prognosis estimates in post-diagnosis counselling.

RevDate: 2020-09-15
CmpDate: 2020-09-15

Lee J, Jin C, Cho SY, et al (2020)

Herbal medicine treatment for Alzheimer disease: A protocol for a systematic review and meta-analysis.

Medicine, 99(33):e21745.

BACKGROUND: Alzheimer disease (AD) is a leading progressive neurodegenerative disease worldwide, but treating it is challenging in clinical practice. This review is aimed at evaluating the efficacy and safety of herbal medicine for treating AD.

METHODS AND ANALYSIS: We will search for randomized controlled trials related to the effect and safety of herbal medicine for AD in the following databases: PubMed, Cochrane Central Register of Controlled Trials, Excerpta Medica Database, China National Knowledge Infrastructure database, Oriental Medicine Advanced Searching Integrated system, Korean Traditional Knowledge Portal, and Citation Information by National Institute for Informatics. The risk of bias will be evaluated using the Cochrane risk-of-bias assessment tool. After screening the studies, a meta-analysis will be performed. The primary outcome will be the Mini-Mental State Examination score. Secondary outcomes will consist of other scales for cognitive function and other aspects, such as behavioral and psychological symptoms and plasma levels of amyloid-β.

RESULTS: This study will provide the current status of evidence for herbal medicine to treat AD.

CONCLUSION: The results of this review will determine the efficacy and safety of herbal medicine for AD.

ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on a review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print.

TRIAL REGISTRATION NUMBER: Research Registry reviewregistry933.

RevDate: 2020-09-01

Maulik M, Vasan L, Bose A, et al (2020)

Amyloid-β regulates gap junction protein Connexin 43 trafficking in cultured primary astrocytes.

The Journal of biological chemistry pii:RA120.013705 [Epub ahead of print].

Altered expression and function of astroglial gap junction protein Connexin 43 (Cx43) has increasingly been associated to neurotoxicity in Alzheimer disease (AD). While earlier studies have examined the effect of increased amyloid-β (Aβ) on Cx43 expression and function leading to neuronal damage, underlying mechanisms by which Aβ modulates Cx43 in astrocytes remain elusive. Here, using mouse primary astrocyte cultures, we have examined the cellular processes by which Aβ can alter Cx43 gap junctions. We show that Aβ25-35 impairs functional gap junction coupling yet increases hemichannel activity. Interestingly, Aβ25-35 increased the intracellular pool of Cx43 with a parallel decrease in gap junction assembly at the surface. Intracellular Cx43 was found to be partly retained in the endoplasmic reticulum-associated cell compartments. However, forward trafficking of the newly synthesized Cx43 that already reached the Golgi was not affected in Aβ25-35 exposed astrocytes. Supporting this, treatment with 4-phenylbutyrate, a well-known chemical chaperone that improves trafficking of several transmembrane proteins, restored Aβ-induced impaired gap junction coupling between astrocytes. We further show that interruption of Cx43 endocytosis in Aβ25-35 exposed astrocytes resulted in their retention at the cell surface in the form of functional gap junctions indicating that Aβ25-35 causes rapid internalization of Cx43 gap junctions. Additionally, in silico molecular docking suggests that Aβ can bind favorably to Cx43. Our study thus provides novel insights into the cellular mechanisms by which Aβ modulates Cx43 function in astrocytes, the basic understanding of which is vital for the development of alternative therapeutic strategy targeting connexin channels in AD.

RevDate: 2020-10-01

Huang WK, Liu CH, Pang ST, et al (2020)

Type of Androgen Deprivation Therapy and Risk of Dementia Among Patients With Prostate Cancer in Taiwan.

JAMA network open, 3(8):e2015189.

Importance: It remains unclear whether androgen deprivation therapy (ADT) is associated with subsequent dementia risk in patients with prostate cancer. There are limited data regarding dementia risk across ADT types.

Objective: To examine the association between all-cause dementia, including Alzheimer disease (AD), and different ADT types in patients with prostate cancer.

This cohort study used linked data from the Taiwan National Cancer Registry, the National Health Insurance Research Database, and the Taiwan National Death Registry. A cohort of 23 651 patients with newly diagnosed prostate cancer between January 1, 2008, and December 31, 2015, was identified and followed up from 1 year after diagnosis until December 31, 2017. Data analysis was performed between January 2019 and May 2020.

Exposures: Patients who received and did not receive ADT, including gonadotropin-releasing hormone (GnRH) agonists, orchiectomy, or antiandrogen monotherapy.

Main Outcomes and Measures: The primary outcomes were all-cause dementia or AD. Stabilized inverse probability of treatment weighting was used to balance baseline covariates. The association between dementia and various ADT types was examined using the Cox proportional hazards model. Furthermore, a multivariate Cox proportional model with age as the time scale was conducted for complementary comparison.

Results: In the cohort of 23 651 male patients (median [interquartile range] age, 73 [66-79] years), 6904 (29.2%) did not receive ADT, 11 817 (50.0%) received GnRH agonists, 876 (3.7%) received orchiectomy, and 4054 (17.1%) received antiandrogen monotherapy. Overall, 1525 patients were diagnosed with incident dementia (1.72 per 100 person-years) during a median (interquartile range) follow-up of 3.46 (1.92-5.51) years. Compared with those who did not receive ADT, those using antiandrogen monotherapy showed an increased risk of dementia (weighted hazard ratio [HR], 1.34; 95% CI, 1.16-1.55) and AD (weighted HR, 1.52; 95% CI, 1.13-2.04). The risk of dementia was similar between GnRH agonist use or orchiectomy and no ADT use (GnRH agonist: weighted HR, 1.13; 95% CI, 1.00-1.28; orchiectomy: 1.00; 95% CI, 0.74-1.37). Several sensitivity analyses revealed consistent findings for both outcomes.

Conclusions and Relevance: In this study, the use of antiandrogen monotherapy was associated with increased risk of dementia or AD, while GnRH agonist use and orchiectomy had no significant difference compared with patients who did not receive ADT. Further prospective studies are warranted to confirm these findings.

RevDate: 2020-08-31

Gupta S, Nair A, Jhawat V, et al (2020)

Unwinding Complexities of Diabetic Alzheimer by Potent Novel Molecules.

American journal of Alzheimer's disease and other dementias, 35:1533317520937542.

Diabetes mellitus is one of the aggressive disorders in global society. No pharmacotherapy is available for permanent diabetes cure, although management is possible with drugs and physical activities. One of the recent complications noticed in type 2 diabetes mellitus includes diabetes-induced Alzheimer. It has been proposed that the possible diabetes-induced Alzheimer could be of type 3 diabetes. A variety of cross-sectional studies have proved that type 2 diabetes mellitus is one of the factors responsible for the pathophysiology of Alzheimer. New drug molecules developed by pharmaceutical companies with adequate neuroprotective effect have demonstrated their efficacy in treatment of Alzheimer in various preclinical diabetic studies. Patients of type 2 diabetes mellitus may show the benefit with existing drugs but may not cause complete cure. Extensive studies are being carried out to find new drug molecules that show their potential as antidiabetic drug and could treat type 2 diabetes-induced Alzheimer as well. This review provides an overview about the recent advancement in pharmacotherapy of diabetes-induced Alzheimer. The pathomechanistic links between diabetes and Alzheimer as well as neurochemical changes in diabetes-induced Alzheimer are also briefed.

RevDate: 2020-09-28

Li G, Sun X, Wan X, et al (2020)

Lactoferrin-Loaded PEG/PLA Block Copolymer Targeted With Anti-Transferrin Receptor Antibodies for Alzheimer Disease.

Dose-response : a publication of International Hormesis Society, 18(3):1559325820917836.

Last few years, struggles have been reported to develop the nanovesicles for drug delivery via the brain-blood barrier (BBB). Novel drugs, for instance, iAβ5, are efficient to inhibit the aggregates connected to the treatment of Alzheimer disease and are being evaluated, but most of the reports reflect some drawbacks of the drugs to reach the brain in preferred concentrations owing to the less BBB penetrability of the surface dimensions. In this report, we designed and developed a new approach to enhance the transport of drug via BBB, constructed with lactoferrin (Lf)-coated polyethylene glycol-polylactide nanoparticles (Lf-PPN) with superficial monoclonal antibody-functionalized antitransferrin receptor and anti-Aβ to deliver the iAβ5 hooked on the brain. The porcine brain capillary endothelial cells were utilized as BBB typically to examine the framework efficacy and toxicity. The cellular uptake of the immuno-nanoparticles with measured conveyance of the iAβ5 peptide was significantly enhanced and associated with Lf-PPN without monoclonal antibody functionalizations.

RevDate: 2020-08-28

Lorettu L, Carpita B, Nivoli A, et al (2020)

Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis.

Clinical neuropharmacology [Epub ahead of print].

Although lithium is widely used as a first-line treatment for mood disorders, its mood-stabilizing effects remain not fully understood. A growing body of data are stressing that lithium seems to show broader properties, including neuroprotective effects. Lithium's ability to inhibit glycogen synthase kinase 3β, an enzyme that participates in the phosphorylation of τ, a microtubule-associated protein, stimulated interest in its possible therapeutic role in Alzheimer disease and other neurodegenerative disorders. Preliminary data also support exploration of lithium's potential therapeutic role in multiple sclerosis, an autoimmune disorder that is associated with co-occurring mood disorders. Lithium is associated with teratogenic risks to the developing fetus; however, recently revised downward estimates of its teratogenic risk of causing fetal cardiac malformation suggest that its potential therapeutic benefit to both mothers with bipolar disorder and their offspring should be considered in at least some cases. A 43-year-old woman previously diagnosed with bipolar disorder and MS was treated with lithium and thyroid hormone supplementation as her sole medications during her pregnancy. The patient remained euthymic throughout her pregnancy and over the course of her 5-year follow-up evaluations on this medication regimen. In addition to her stable mood, there has been no symptomatic progression or relapse of her MS, and her daughter continues to develop normally.The case supports consideration of balancing lithium's mood-stabilizing benefit with its known teratogenic risk during pregnancy. The case also supports exploration of possible additional benefit in the context of MS co-occurring with bipolar disorder.

RevDate: 2020-08-30

Wei W, Wang Y, Liu Y, et al (2020)

Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice.

Alzheimer's research & therapy, 12(1):102.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. The important influence of congenital genetic aberrations on the development of AD provides a novel opportunity to initiate prenatal to early postnatal pharmacological treatment to address the role of this critical period of brain development in the disease.

METHODS: We investigated for the first time the effect of oral treatment during prenatal to early postnatal development with a neurotrophic compound, P021 (Ac-DGGLAG-NH2), on neurobehavior and AD-like pathology in 3xTg-AD, a transgenic mouse model of AD. The transgenic and control wild-type female mice were treated from prenatal day 8 to postnatal day 21 with a custom-made diet containing P021 or a vehicle diet, followed by a standard diet. AD-type cognitive function and pathological features were studied during adulthood and old age.

RESULTS: The P021 treatment rescued cognitive deficits at 4 months, reduced abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology-associated sites, and decreased Aβ plaque load at 22 months in 3xTg-AD mice. Prenatal to early postnatal treatment with P021 also ameliorated certain markers of postsynaptic deficits, including PSD-95 levels and CREB activity, and decreased one measure of neuroinflammation, GFAP level in the brain at 4 and 22 months in 3xTg mice.

CONCLUSIONS: These findings suggest that neurotrophic impairment during early development can be one of the etiopathogenic factors of AD and that the neurotrophic peptide mimetic is a potential early prevention strategy for this disease.

RevDate: 2020-09-11

Suresh J, Khor IW, Kaur P, et al (2020)

Shared signaling pathways in Alzheimer's and metabolic disease may point to new treatment approaches.

The FEBS journal [Epub ahead of print].

'A peculiar severe disease process of the cerebral cortex' are the exact words used by A. Alzheimer in 1906 to describe a patient's increasingly severe condition of memory loss, changes in personality, and sleep disturbance. A century later, this 'peculiar' disease has become widely known as Alzheimer's disease (AD), the world's most common neurodegenerative disease, affecting more than 35 million people globally. At the same time, its pathology remains unclear and no successful treatment exists. Several theories for AD etiology have emerged throughout the past century. In this review, we focus on the metabolic mechanisms that are similar between AD and metabolic diseases, based on the results from genome-wide association studies. We discuss signaling pathways involved in both types of disease and look into new optogenetic methods to study the in vivo mechanisms of AD.

RevDate: 2020-08-28

Dehlin M, Kapetanovic M, Svärd A, et al (2020)

[Consequences of Gout and Hyperuricemia].

Lakartidningen, 117: pii:F3HI.

Hyperuricemia (HU) and gout are strongly associated with CVD, associations that are most likely due to shared etiologies rather than causality. HU is for example causally related to the metabolic syndrome and in particular to obesity. Gout and HU can both be caused by and lead to decreased kidney function. On the other hand, there are observational data suggesting that HU may protect against neurodegenerative diseases such as Alzheimer and Parkinson's disease. Ongoing RCTs with urate and urate lowering therapy (ULT) will help to resolve some of these controversies. Nevertheless, gout is a "curable disease" by ULT, a treatment which in adequate doses may also have positive effect on several associated co-morbidities.

RevDate: 2020-09-28

Izrael M, Slutsky SG, M Revel (2020)

Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease.

Frontiers in neuroscience, 14:824.

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.

RevDate: 2020-08-26

Wong W (2020)

Economic burden of Alzheimer disease and managed care considerations.

The American journal of managed care, 26(8 Suppl):S177-S183.

Alzheimer disease is the most common cause of dementia and the fifth leading cause of death in adults older than 65 years. The estimated total healthcare costs for the treatment of Alzheimer disease in 2020 is estimated at $305 billion, with the cost expected to increase to more than $1 trillion as the population ages. Most of the direct costs of care for Alzheimer disease are attributed to skilled nursing care, home healthcare, and hospice care. Indirect costs of care, including quality of life and informal caregiving, are likely underestimated and are associated with significant negative societal and personal burden. Managed care organizations are in a unique position to develop utilization strategies that would positively impact early diagnosis and treatment to lead to better outcomes and lower costs for patients, caregivers, and the healthcare system. Additionally, the recent inclusion of Alzheimer disease diagnoses into risk corridor calculations by the Centers for Medicare & Medicaid Services may encourage Medicare Advantage organizations to invest in programs that aid in its early detection and diagnosis.

RevDate: 2020-08-26

Marasco RA (2020)

Current and evolving treatment strategies for the Alzheimer disease continuum.

The American journal of managed care, 26(8 Suppl):S167-S176.

The burden of Alzheimer disease (AD) on the US healthcare system is substantial and increasing. AD progresses along a continuum from preclinical disease characterized by normal cognition and abnormal brain biomarkers to mild cognitive impairment and then clinically apparent dementia. Diagnosis early in the AD continuum has benefits for patients and caregivers and appears cost-effective, but often, the clinical diagnosis of AD may be delayed. Currently available biomarkers include β-amyloid positron emission tomography and cerebrospinal fluid tests. Collectively, they are expensive, may lead to adverse effects, are not widely available, and are not suited for primary care. Currently available treatment options, cholinesterase inhibitors and memantine, do not alter disease progression, but can help with some symptoms. Benefits of currently available treatments on cognition are difficult to quantify and are offset by a burden of adverse effects that often go unrecognized. More accurate diagnostic biomarkers and disease-modifying drug therapies are critical unmet needs of patients with AD despite decades of clinical research. Because many phase 3 clinical trials that enrolled patients with symptomatic AD have failed, researchers believe that disease-modifying treatment is more likely to demonstrate benefit when utilized early in the disease continuum. Within the past few years, significant achievements that will advance clinical trials in early AD include the Research Framework to define and stage the AD continuum, FDA guidance on study design in early AD, and development of scales to measure cognition that are suitable for early AD. In October 2019, the AD community was re-invigorated by unexpected news that a Biologics License Application will be submitted for aducanumab to treat AD. This article explores the current state of biomarker-driven drug development across the AD continuum and reviews investigational drugs in phase 2/3 clinical development for AD.

RevDate: 2020-09-28

Xuan WT, Wang H, Zhou P, et al (2020)

Berberine ameliorates rats model of combined Alzheimer's disease and type 2 diabetes mellitus via the suppression of endoplasmic reticulum stress.

3 Biotech, 10(8):359.

This study is aimed to investigate the protective effect against type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) of Berberine (BBR), and the underlying mechanism of action is explored. We established a rat model of combined AD and T2DM and used it to investigate the effect of BBR (150 mg/kg) on the course of these pathologies. The Morris water maze, biochemical analysis, hematoxylin-eosin staining, immunohistochemical study, immunofluorescent staining, TUNEL assay, RT-qPCR and western blot were used to reveal the effect of BBR on blood glucose, lipid changes, hippocampal injuries and cognitive impairment. The results showed that BBR could alleviate memory deficits, restore the disordered arrangement of nerve cells, the damage of neurons, improve TUNEL-positive cells and decrease the elevated levels of fasting blood glucose, triglyceride, total cholesterol and glycosylated serum protein levels in Alzheimer diabetic rats. Moreover, BBR treatment reduces the transcription of mRNAs and expression of proteins related to endoplasmic reticulum (ER) stress. These findings conclude that BBR can protect neurons by inhibiting the pathway of ER stress and thereby play an essential role in the preventive and therapeutic of AD and T2DM.

RevDate: 2020-08-21

Pandey M, Choudhury H, Verma RK, et al (2020)

Nanoparticles Based Intranasal Delivery of Drug to Treat Alzheimer's Disease: A Recent Update.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-109274 [Epub ahead of print].

Alzheimer Association Report (2019) stated that the 6th primary cause of death in the USA is Alzheimer's disease (AD) which leads to behaviour and cognitive impairment. Nearly 5.8 million peoples of all ages in the USA have suffered from this disease, including 5.6 million elderly populations. The statistics of the progression of this disease is similar to the global scenario. Still, the treatment of AD is limited to a few conventional oral drugs which often fail to deliver the adequate amount of drug in the brain. The reduction in the therapeutic efficacy of anti-AD drug is due to poor solubility, existence to the blood-brain barrier and low permeability. In this context, nasal drug delivery emerges as a promising route for the delivery of large and small molecular drugs for the treatment of AD. This promising pathway delivers the drug directly into the brain via an olfactory route which leads to the low systemic side effect, enhanced bioavailability, and higher therapeutic efficacy. However, few setbacks such as mucociliary clearance and poor drug mucosal permeation limit its translation from the laboratory to the clinic. Above stated limitation could be overcome by the adaption of nanoparticle as a drug delivery carrier which may lead to prolong delivery of drugs with better permeability and high efficacy. This review highlights the latest work on the development of promising nanoparticles (NPs) via intranasal route for the treatment of AD. Additionally, the current update in this article will drag the attention of the researcher working on these fields and facing challenges in practical applicability.

RevDate: 2020-08-19

Singh M, Singh SP, Yadav D, et al (2020)

Targeted delivery for neurodegenerative disorders using gene therapy vectors: Gen next therapeutic goals.

Current gene therapy pii:CGT-EPUB-109175 [Epub ahead of print].

The technique of gene therapy, ever since its advent nearly fifty years ago, has been utilized by scientists as a po-tential treatment option for various disorders. This review discusses some of the major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), Motor neuron diseases (MND), Spinal muscular atrophy (SMA), Huntington's disease (HD), Multiple sclerosis (MS) etc. and their underlying genetic mechanisms along with therole that gene therapy can play in combating them. The pathogenesis and the molecular mechanisms specifying the altered gene ex-pression of each of these NDDs has also been discussed in elaboration. The use of gene therapy vectors can prove to be an effective tool in the field of curative modern medicine for the generations to come. Therefore, consistent efforts and pro-gressive research towards its implementation can provide us with powerful treatment options for disease conditions that have so far been considered as incurable.

RevDate: 2020-08-12

Övey İS, M Nazıroğlu (2020)

Effects of homocysteine and memantine on oxidative stress related TRP cation channels in in-vitro model of Alzheimer's disease.

Journal of receptor and signal transduction research [Epub ahead of print].

Memantine (MEM) has been used to treat patients with Alzheimer' disease though inhibition of reactive oxygen species (ROS), Ca2+ entry and glutamate receptor. The Ca2+ permeable TRPA1, TRPM2 and TRPV1 channels are activated in the hippocampus by ROS, and antioxidant MEM as a potent TRPA1, TRPM2 and TRPV1 channel antagonist may reduce Aβ-induced oxidative stress and apoptosis in the neurons. In the current study, we investigated the neuroprotective properties of MEM in Aβ-induced hippocampal neuron cultures. Freshly isolated hippocampal neurons of mice were divided into eight groups as control, Aβ, Hcy, MEM, Aβ + Hcy, Aβ + Hcy + MEM, Aβ + MEM and Hcy + MEM. The neurons were exposed to incubated with Aβ (20 µM for 24 h), Hcy (250 µM for 30 min) and MEM (10 µM for 24 h). TRPA1, TRPM2 and TRPV1 of the eight groups were further stimulated by cinnamaldehyde, cumene hydyroperoxide and capsaicin, respectively although they were further inhibited by AP-18, N-(p-Amylcinnamoyl) anthranilic acid (ACA) and capsazepine (CPZ). The [Ca2+] concentration, apoptosis, caspase 3, caspase 9 activations, mitochondrial membrane depolarization and intracellular ROS production values in the neurons were higher in Aβ and Hcy groups than in control although they were lower in the MEM group than in Aβ and Hcy groups. The values were further decreased by MEM + AP-18, MEM + CPZ and MEM + ACA treatments as compared to MEM only. Aβ and Hcy-induced decrease of cell viability level was increased by MEM treatment although Aβ and Hcy-induced increase of caspase 3, caspase 9, PARP1, TRPA1, TRPM2 and TRPV1 expression levels were decreased by MEM treatments. In conclusion, TRPA1, TRPM2 and TRPV1 channels are involved in Aβ and Hcy-induced neuronal death, and modulation of the activity of these channels by MEM treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca2+ entry.

RevDate: 2020-09-21

Haghighijoo Z, Akrami S, Saeedi M, et al (2020)

N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer's disease.

Bioorganic chemistry, 103:104146.

Alzheimer's disease (AD) is the most common form of dementia. While drugs that target several pathways underlying AD have been proposed, effective treatments remain to be discovered. BACE1, an enzyme associated with AD progression, is a promising target for developing anti-Alzheimer drugs. To find novel multifunctional anti-Alzheimer agents, we designed and synthesized a series of new substituted benzyl-1H-1,2,3-triazol-4-yl-N-cyclohexylimidazo[1,2-a]pyridin-3-amine. The in vitro screening results revealed that most of the compounds exhibited moderate to potent BACE1 and BuChE inhibitory and antioxidant activities. Compounds 7f and 7g, bearing dichloro (2,3-Cl2 and 3,4-Cl2) moieties on the benzyl pendant were selected as the most active compounds in our BACE1 inhibitory assay with respective IC50 values of about 12 and 8.9 μM. In addition, compounds 7g and 7h (4-bromo derivative) showed the highest BuChE inhibitory activity with IC50 of 3.2 and 2.5 µM, respectively. Compound 7g also possessed antioxidant activity with an IC50 value of 10.2 μM and metal chelation potential. Moreover, docking studies were performed to investigate the possible mechanism of inhibition. Taken together, we demonstrate that N-cyclohexylimidazo[1,2-a]pyridine containing triazole motif derivatives deserve further investigation for anti-Alzheimer drug development.

RevDate: 2020-09-22

Grill JD, Raman R, Ernstrom K, et al (2020)

Short-term Psychological Outcomes of Disclosing Amyloid Imaging Results to Research Participants Who Do Not Have Cognitive Impairment.

JAMA neurology [Epub ahead of print].

Importance: The goal of preclinical Alzheimer disease (AD) clinical trials is to move diagnosis and treatment to presymptomatic stages, which will require biomarker testing and disclosure.

Objective: To assess the short-term psychological outcomes of disclosing amyloid positron emission tomography results to older adults who did not have cognitive impairment.

This observational study included participants who were screening for a multisite randomized clinical trial that began on February 28, 2014, and is anticipated to be completed in 2022. Participants aged 65 to 85 years who had no known cognitive impairments underwent an amyloid positron emission tomography scan and learned their result from an investigator who used a protocol-specified process that included prescan education and psychological assessments. This report compares participants with elevated amyloid levels with at least 1 available outcome measure with participants who did not have elevated amyloid levels who enrolled in an observational cohort study and received further evaluations. Data were collected from April 2014 to December 2017 and analyzed from March 2019 to October 2019.

Exposures: A personal biomarker result described as either an elevated or not elevated amyloid level.

Main Outcomes and Measures: To assess the immediate and short-term psychological outcome of disclosure, the following validated measures were used: the Geriatric Depression Scale, the state items from the State-Trait Anxiety Inventory, and the Columbia Suicide Severity Rating Scale, as well as the Concerns About AD Scale and the Future Time Perspective Scale to assess changes in participants' perceived risk for AD and perceived remaining life span, respectively.

Results: A total of 1167 participants with elevated amyloid levels and 538 participants with not elevated amyloid levels were included. Participants had a mean (SD) age of 71.5 (4.7) years, 1025 (60.1%) were women, and most were white (1611 [94.5%]) and non-Latino (1638 [96.1%]). Compared with participants who learned that they had a not elevated amyloid result, individuals who learned of an elevated amyloid result were no more likely to experience short-term increases in depression (mean [SD] change in the Geriatric Depression Scale score, 0.02 [1.3] vs 0.04 [1.3]; P = .90), anxiety (mean [SD] change in State-Trait Anxiety Inventory score, -0.02 [3.2] vs -0.15 [3.0]; P = .65), or suicidality (mean [SD] change in the Columbia Suicide Severity Rating Scale score, 0.0 [0.4] vs -0.01 [0.5]; P = .67). Participants with elevated amyloid levels had increased Concern About AD scores (raw change in scores: elevated amyloid group, 0.8 [3.9]; not elevated amyloid group, -0.4 [3.8]; P < .001). Participants with not elevated amyloid levels experienced a slight increase in Future Time Perspective score(mean [SD] score, 1.15 [7.4] points; P < .001); there was no change in time perspective among those receiving an elevated amyloid result (mean [SD] score, 0.33 [7.8] points).

Conclusions and Relevance: In this observational preclinical AD study, participants who learned they had elevated amyloid levels did not experience short-term negative psychological sequelae compared with persons who learned they did not have elevated amyloid levels.

RevDate: 2020-09-18

Peng HB, Noh K, Pan SR, et al (2020)

Human Amyloid-β40 Kinetics after Intravenous and Intracerebroventricular Injections and Calcitriol Treatment in Rats In Vivo.

Drug metabolism and disposition: the biological fate of chemicals, 48(10):944-955.

Amyloid-β peptides of 40 and 42 amino acid lengths, which are synthesized in neurons and degraded in the brain and liver, have the potential to aggregate and form neuritic plaques in Alzheimer disease. The kinetics of human amyloid-β (hAβ) 40 were examined in the rat pursuant to intravenous and intracerebroventricular administration after pretreatment with calcitriol, the active vitamin D receptor ligand (6.4 nmol·kg-1 in 0.3 ml corn oil every other day for four intraperitoneal doses) to induce P-glycoprotein (P-gp) and enhance hAβ40 brain efflux. The interference of hAβ40 by media matrix that suppressed absorbance readings in the ELISA assay was circumvented with use of different calibration curves prepared in Standard Dilution Buffer, undiluted, 10-10,000 or 5-fold diluted plasma, or artificial cerebrospinal fluid. Simultaneous fitting of hAβ40 plasma and cerebrospinal fluid (CSF) data after intravenous and intracerebroventricular administration were described by catenary-mammillary models comprising of a central and two peripheral compartments, the brain, and one to four CSF compartments. The model with only one CSF compartment (model I) best fitted the intravenous data that showed a faster plasma decay t1/2 and slower equilibration between plasma and brain/CSF. Calcitriol induction increased the brain efflux rate constant, k41 (1.8-fold), at the blood-brain barrier when compared with the control group, as confirmed by the 2-fold (P < 0.05) increase in brain P-gp relative protein expression. SIGNIFICANCE STATEMENT: An accurate description of the kinetic behavior of human amyloid-β (hAβ) 40 is needed in defining the toxic peptide as a biomarker of Alzheimer disease. Modeling of hAβ40 data after intravenous and intracerebroventricular administration to the rat revealed an initially faster plasma half-life that reflected faster peripheral distribution but slower equilibration between plasma and brain/cerebrospinal fluid even with calcitriol pretreatment that increased P-glycoprotein protein expression and enhanced efflux clearance from brain.

RevDate: 2020-08-25

Fu Y, Yang Y, Shi J, et al (2020)

Acori tatarinowii rhizoma extract ameliorates Alzheimer's pathological syndromes by repairing myelin injury and lowering Tau phosphorylation in mice.

Die Pharmazie, 75(8):395-400.

It has been shown that Acori tatarinowii rhizoma (ATR) extract can improve cognitive functions in Alzheimer Diseas (AD) patients or animal models. In this study, we have examined the activity of ATR in 3×Tg-AD model mice with different comprehensive behavioral tests like the Morris water maze and Y-maze test assay for behavior. Moreover, we performed LFB staining for myelin determination in the AD model mouse. By analyzing different pathways, we determined key proteins that are beneficial for ameliorating AD syndrome in the mouse. Periluminally, ATR treatment improved the learning and memory ability that was determined by comprehensive behavioral tests. Moreover, treatment reduces the p-Tau accumulation in the 3×Tg-AD mouse and the level of p-Tau accumulation was at per with the wildtype control mouse and improves the myelin lining in 3×Tg-AD mouse. In conclusion, our results indicate that ATR-treatment can improve the learning ability of AD model mice and the hyperphosphorylation of Tau protein was decreased. ATR can protect myelin lining from damage in AD syndrome.

RevDate: 2020-08-04

Işık M, Ş Beydemir (2020)

The impact of some phenolic compounds on serum acetylcholinesterase: kinetic analysis of an enzyme/inhibitor interaction and molecular docking study.

Journal of biomolecular structure & dynamics [Epub ahead of print].

In the treatment of Alzheimer's disease (AD), it is important to develop alternative cholinesterase inhibitors with antioxidant properties that will reduce acetylcholine deficiency and free radical formation. The aim of this study was to investigate the effect of hydroquinone, 4-hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, caffeic acid, vanillic acid and chlorogenic acid against acetylcholinesterase (AChE), partially purified from serum. Binding of compounds with effective inhibitory potential to the AChE active site as competitive was illuminated by molecular docking. Hydroquinone, chlorogenic acid and 4-hydroxybenzoic acid have been found to have higher inhibitory potential than others against the AChE. IC50 and KI values of the phenolic compounds against AChE were found in the range of 0.26 ± 0.01-36.34 ± 2.72 mM and 0.72 ± 0.00-29.23 ± 2.62 mM, respectively. The effectiveness of the compounds has been associated with its structure. Consequently, the phenolic compounds, which have AChE inhibitory potential and antioxidant properties, can be considered as alternative drugs in the treatment of AD. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-09-28

Naing HL, SP Teo (2020)

Impact of Hypertension on Cognitive Decline and Dementia.

Annals of geriatric medicine and research, 24(1):15-19.

Dementia reduces a person's ability to perform their activities of daily living and is the leading cause of morbidity worldwide. While most preventive measures are ineffective in reducing dementia risk, active treatment of hypertension in middle-aged and older adults without dementia may reduce the incidence of dementia. Hypertension is associated with vascular dementia but may also affect the manifestations of Alzheimer disease. Observational studies support the association between hypertension and white matter lesions, hippocampal atrophy, and cognitive decline. Both increased and decreased blood pressure were related to the development of white matter lesions. Cohort studies showed that hypertension treatment and treatment duration were associated with lower cognitive decline. This review describes findings from randomized controlled studies on the effects of antihypertensives on cognitive decline. Only the Systolic Hypertension in Europe (Syst-Eur) trial using calcium-channel blockers demonstrated a significant reduction in dementia incidence. Further studies are required to evaluate the long-term benefits of antihypertensive treatment in dementia.

RevDate: 2020-09-28

Ahmed Z, Aziz S, Hanif M, et al (2020)

Phytochemical screening and enzymatic and antioxidant activities of Erythrina suberosa (Roxb) bark.

Journal of pharmacy & bioallied sciences, 12(2):192-200.

Background: This study aimed to evaluate the phytochemicals screening of Erythrina suberosa (Roxb) bark and to analyze the enzymatic activities of its various organic fractions.

Materials and Methods: Crude methanolic fraction of E. suberosa (Roxb) bark and its respective fractions were screened for the presence of different phytochemicals with different reagents. On the basis of increasing order of polarity, different organic solvents were used to obtain different fractions. Enzymatic studies were performed on crude methanolic extract of the plant. All the assays were performed under standard in vitro conditions.

Results: The phytochemical analysis shows the presence of alkaloids, phenols, triterpenoids, phytosterols, and flavonoids. Phenolic compounds and flavonoids are the major constituents of the plant. In anticholinesterase assay, the percent inhibition of standard drug (eserine) was 91.27 ± 1.17 and the half maximal inhibitory concentration (IC50) was 0.04 ± 0.0001. For α-glucosidase inhibition, the IC50 value for Dichloromethane fraction was 8.45 ± 0.13, for Methanol fraction it was 64.24 ± 0.15, and for aqueous fraction it was 42.62 ± 0.17 as compared with standard IC50 that is 37.42 (acarbose). Furthermore, results show that all fractions have potential against anti-urease enzyme, but DCM fraction of crude aqueous extract has significant IC50 value (45.26 ± 0.13) than other fractions.

Conclusion: Keeping in view all the results, it is evident that the plant can be used in future for formulating effective drugs against many ailments. Secondary metabolites and their derivatives possess different biological activities, for example, .g. flavonoids in cancer, asthma, and Alzheimer. Furthermore, the extracts of this plant can be used in their crude form, which is an addition to the complementary and alternative treatment strategies.

RevDate: 2020-09-22

Hasegawa T, Kosoku Y, Sano Y, et al (2020)

Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study.

Journal of Alzheimer's disease : JAD, 77(2):773-780.

BACKGROUND: In the treatment of Alzheimer's disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD.

OBJECTIVE: Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD.

METHODS: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients' plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases.

RESULTS: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%.

CONCLUSION: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.

RevDate: 2020-08-01

Abdeljalil AB, de Mauléon A, Baziard M, et al (2020)

Antidepressant Use and Progression of Mild to Moderate Alzheimer's Disease: Results from the European ICTUS Cohort.

Journal of the American Medical Directors Association pii:S1525-8610(20)30539-9 [Epub ahead of print].

OBJECTIVES: Neuropsychiatric symptoms (NPS) are a core and troubling feature among patients with Alzheimer disease (AD). Because of growing safety warnings against antipsychotics, the use of antidepressants (ATD) in AD has increased extensively. We investigated the potential long-term associations between ATD exposure and functional and cognitive progression in patients with mild to moderate AD.

DESIGN: Two-year prospective multicenter cohort ICTUS (Impact of Cholinergic Treatment USe) study with biannual assessments.

SETTING: Twenty-nine memory clinics from 12 European countries.

PARTICIPANTS: Community-dwelling patients with mild to moderate AD.

METHODS: Global cognitive function was measured using the Mini Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Functional impairment was measured using the Activities of Daily Living (ADL). Assessments were performed biannually for 2 years. Antidepressant exposure was defined by an ATD prescription for a minimum period of 6 months. Linear mixed models were used to study the associations between ATD exposure and cognitive and functional progression.

RESULTS: Antidepressant exposure was not associated with cognitive decline [MMSE: β-coefficients of the linear mixed models (Coef) = 0.06, 95% confidence interval (CI) -0.65 to 0.76, P = .87; ADAS-Cog: Coef = -13.9, 95% CI -34.80 to 7.03, P = .19] or with functional decline (ADL: Coef = -0.05, 95% CI -0.21 to 0.09, P = .48) at 2-year follow-up. Antipsychotic exposure at baseline was associated with a greater functional decline in the ADL score (Coef = -0.39, 95% CI - 0.68 to 0.10, P < .01).

CONCLUSIONS AND IMPLICATIONS: Antidepressant exposure was not associated with a faster rate of cognitive or functional decline in patients with mild to moderate AD. Antidepressants might be appropriate alternatives to antipsychotics in the management of NPS in mild to moderate AD.

RevDate: 2020-09-16

Sugin LJS, Murugesan A, Bindu M, et al (2020)

Roflumilast: A potential drug for the treatment of cognitive impairment?.

Neuroscience letters, 736:135281.

Phosphodiesterase-4 regulates the intracellular level of cAMP. Roflumilast, a selective PDE-4 inhibitor was the first agent in this class to have reached the market for patients with chronic obstructive pulmonary disease worldwide. Numerous preclinical evidences indicate the role of PDE-4 inhibitors in reversal of ageing-related alterations induced in animal models by various pharmacological agents, overexpression of mutant forms of human amyloid precursor proteins and in aging, as well. Roflumilast was capable of decreasing PDE-4B and 4D subtypes with an increase in the expression of pCREB and BDNF in hippocampus of rats. The beneficial effects of roflumilast on cognition are believed to be mediated through the above-mentioned cellular effects. Recently, Jabaris et al had shown that roflumilast has improved the short and long-term memory in rodents. Several lines of evidence indicate that targeting PDE-4 inhibition might offer novel approaches in the treatment of age-associated memory impairment and in Alzheimer's disease. Likewise, in a recent report, roflumilast improved the memory functions in humans after administration of 100 μg of the drug, without the typical side effects of PDE-4 inhibitors, which might offer a novel therapeutic option for the treatment of cognitive impairment and Alzheimer disease. In the current article, the author reviews the most recent evidences demonstrating the beneficial effects of roflumilast on learning and memory in animal models and humans.

RevDate: 2020-08-28

Sun Y, Wang Y, Chen ST, et al (2020)

Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21.

Theranostics, 10(18):8430-8445.

A viewpoint considering Alzheimer's disease (AD) as "type 3 diabetes" emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid β-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.

RevDate: 2020-09-28

Varano F, Catarzi D, Vigiani E, et al (2020)

Piperazine- and Piperidine-Containing Thiazolo[5,4-d]pyrimidine Derivatives as New Potent and Selective Adenosine A2A Receptor Inverse Agonists.

Pharmaceuticals (Basel, Switzerland), 13(8):.

The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A2A AR binding affinity (Ki = 8.62 nM) as well as inverse agonist potency (IC50 = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles.

RevDate: 2020-10-12

Lushchekina SV, P Masson (2020)

Slow-binding inhibitors of acetylcholinesterase of medical interest.

Neuropharmacology, 177:108236.

Certain ligands slowly bind to acetylcholinesterase. As a result, there is a slow establishment of enzyme-inhibitor equilibrium characterized by a slow onset of inhibition prior reaching steady state. Three mechanisms account for slow-binding inhibition: a) slow binding rate constant kon, b) slow ligand induced-fit following a fast binding step, c) slow conformational selection of an enzyme form. The slow equilibrium may be followed by a chemical step. This later that can be irreversible has been observed with certain alkylating agents and substrate transition state analogs. Slow-binding inhibitors present long residence times on target. This results in prolonged pharmacological or toxicological action. Through several well-known molecules (e.g. huperzine) and new examples (tocopherol, trifluoroacetophenone and a 6-methyluracil alkylammonium derivative), we show that slow-binding inhibitors of acetylcholinesterase are promising drugs for treatment of neurological diseases such as Alzheimer disease and myasthenia gravis. Moreover, they may be of interest for neuroprotection (prophylaxis) against organophosphorus poisoning. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

RevDate: 2020-09-17
CmpDate: 2020-09-17

Tanaka N, Okuda M, Nishigaki T, et al (2020)

Development of a brain-permeable peptide nanofiber that prevents aggregation of Alzheimer pathogenic proteins.

PloS one, 15(7):e0235979.

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidβ in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid βby trapping amyloid β onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.

RevDate: 2020-07-24

Mascarenhas AMS, de Almeida RBM, de Araujo Neto MF, et al (2020)

Pharmacophore-based virtual screening and molecular docking to identify promising dual inhibitors of human acetylcholinesterase and butyrylcholinesterase.

Journal of biomolecular structure & dynamics [Epub ahead of print].

The dual inhibition of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) plays an important role in Alzheimer's disease treatment. Thus, this study aims identify promising dual inhibitors against hAChE and hBuChE by in silico approaches (pharmacophore-based virtual screening and molecular docking). Ten 3 D pharmacophore models for dual inhibitors using default genetic parameters were built by GALAHAD™ available on SYBYL-X 2.0. Validation steps were carried out according to Energy (<100.0 kcal/mol), Pareto = 0, Area under the ROC Curve (>0.70), Boltzmann-Enhanced Discrimination of ROC curve (BEDROC >0.50) and structure-activity relationship (SAR) for known inhibitors. The best dual pharmacophore model based on internal/external statistical parameters and SAR data (one hydrogen bond acceptor, two hydrogen bond donors and four hydrophobic centers) was employed in virtual screening at Sigma-Aldrich® subset (n = 214,446) of ZINC database by UNITY module of SYBYL-X 2.0. According to superposition values (QFIT), the best ranked compounds were prioritized for molecular docking and partition coefficient analysis (clog p < 5.0). 37 top-ranked compounds (QFIT > 64.22) from pharmacophore model showed affinity in hAChE (-10.2 < Affinity energy < -6.3 kcal/mol) and hBuChE (-10.9 < Affinity energy < -2.3 kcal/mol) binding sites. Next, liposolubity prediction and commercially available showed that ZINC43198636, ZINC43198637 and ZINC00390718 can be potential dual inhibitors against hAChE and hBuChE. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-09-28

Joseph CR (2020)

Novel MRI Techniques Identifying Vascular Leak and Paravascular Flow Reduction in Early Alzheimer Disease.

Biomedicines, 8(7):.

With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood-brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments. Ideally, human medication trials require a minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes. We will review the known physiology and anatomy of the BBB system, and its relationship to the glymphatic system and the microglial surveillance system. Dysfunction of this tripart system occurring in preclinical Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments. High-resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non-invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.

RevDate: 2020-07-17

Ghai R, Nagarajan K, Arora M, et al (2020)

Current Strategies and Novel Drug Approaches for Alzheimer Disease.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-108224 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a chronic devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc are being used to manage the symptoms of Alzheimer's disease.

OBJECTIVE: The paper's objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals.

MATERIALS & METHODS: Enormous literature survey was conducted and published articles of PUBMED, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer's disease.

RESULTS & CONCLUSION: Currently, several strategies are being investigated for the treatment of Alzheimer's disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.

RevDate: 2020-07-23
CmpDate: 2020-07-23

Sokolova SV, Sozarukova MM, Khannanova AN, et al (2020)

[Antioxidant status in patients with paranoid schizophrenia and Alzheimer disease].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 120(6):82-87.

OBJECTIVE: To study the antioxidant profile of blood plasma in patients with paranoid schizophrenia and Alzheimer disease (AD).

MATERIAL AND METHODS: Thirty-three patients with paranoid schizophrenia and 18 patients with AD were included in the study. Patients with schizophrenia were stratified into two subgroups by response to therapy. The indicators of the antioxidant profile were determined using methods based on chemiluminometry and spectrofluorimetry.

RESULTS: Systemic oxidative stress due to insufficiency of low molecular weight plasma antioxidants is not determined neither in AD nor in treatment resistant schizophrenia. At the same time, a «thiol» oxidative stress, which indirectly indicates a deficiency of the glutathione system, is present in both groups. In patients with paranoid schizophrenia responsive to treatment, systemic oxidative stress is more pronounced and «thiol» oxidative stress is less significant. Among the antipsychotics studied, haloperidol, zuclopenthixol, risperidone and ziprasidone do not exhibit antioxidant properties, but periciazine, clozapine and especially chlorpromazine exhibit strong antioxidant properties, but they unlikely affect the antioxidant potential of blood plasma.

CONCLUSIONS: The glutathione part of the antioxidant system is mostly affected, but systemic oxidative stress is not significant in patients with treatment resistant paranoid schizophrenia and AD. Oxidative disorders are more pronounced in treatment responsive paranoid schizophrenia.

RevDate: 2020-07-21

Jin N, Ziyatdinova S, Gureviciene I, et al (2020)

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs.

Scientific reports, 10(1):11851.

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

RevDate: 2020-07-21

Koch G, Motta C, Bonnì S, et al (2020)

Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial.

JAMA network open, 3(7):e2010372.

Importance: Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD).

Objective: To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD.

This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019.

Interventions: A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47).

Main Outcomes and Measures: The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography.

Results: Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group.

Conclusions and Relevance: In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living.

Trial Registration: ClinicalTrials.gov Identifier: NCT03250741.

RevDate: 2020-07-14

Liao Z, Cheng L, Li X, et al (2020)

Meta-analysis of Ginkgo biloba Preparation for the Treatment of Alzheimer's Disease.

Clinical neuropharmacology, 43(4):93-99.

OBJECTIVE: The objective of this study was to investigate the efficacy and safety of Ginkgo biloba preparation for the treatment of Alzheimer disease (AD).

METHODS: Both English (PubMed, Embase, Cochrane Library databases, and the Cochrane Controlled Trials Register) and Chinese (WanFang, Chinese Biomedical, CNKI, and VIP databases) databases were systematically and independently searched by 2 authors from their inception until July 3, 2019. All relevant studies included AD patients who were treated with Ginkgo biloba. The efficacy and safety of the medicine were used as the main measurement index.

RESULTS: Seven studies (N = 939) were identified and analyzed. When compared with placebo, Ginkgo biloba showed exact validity in cognitive function and global clinical assessment (cognitive function section: risk ratio = 1.98, 95% confidence interval = 1.52-2.59, Z = 5.12, P < 0.001; according to Clinical Global Impression Change: odds ratio = 3.119, 95% confidence interval = 2.206-4.410, Z = 6.44, P < 0.001). Adverse events were mild.

CONCLUSIONS: Ginkgo biloba preparation has reliable efficacy of cognitive function and global clinical assessment and safety in the treatment of AD.

RevDate: 2020-07-11

Rajabi F, Gusbeth C, Frey W, et al (2020)

Nanosecond pulsed electrical fields enhance product recovery in plant cell fermentation.

Protoplasma pii:10.1007/s00709-020-01534-9 [Epub ahead of print].

The potential of pharmacologically active secondary plant metabolites is limited by the low yield from often rare plants, and the lack of economically feasible chemical synthesis of these complex compounds. Plant cell fermentation offers an alternative strategy to overcome these constraints. However, the efficiency of this approach is limited by intracellular sequestration of the products, such that continuous bioprocessing is not possible. As a precondition for such a, more attractive, continuous process, it is of great importance to stimulate the export of the product into the medium without impairing viability and, thus, the productivity of the cells. Using nicotine alkaloids of tobacco as a case study, an alternative strategy is explored, where nanosecond pulsed electric fields (nsPEFs) are applied for the efficient downstream recovery of the products. To maintain cell viability and allow for the further use of biomass, cells were exposed to strong (1-20 kV·cm-1), but very short (10-100 ns) electric pulses, which leads to a temporary permeabilisation of cell membranes. Using two transgenic cell lines, where two key genes involved in the metabolism of the anti-Alzheimer compound nornicotine were overexpressed, we could show that this nsPEF treatment improved the partitioning of some nicotine alkaloids to the culture medium without impairing viability, nor the synthesis of alkaloids. However, this release was only partial and did not work for nornicotine. Thus, nsPEFs produced a fractionation of alkaloids. We explain this electrofractionation by a working model considering the differential intracellular compartmentalization of nicotineic alkaloids.

RevDate: 2020-07-28

Kısa D, Korkmaz N, Taslimi P, et al (2020)

Bioactivity and molecular docking studies of some nickel complexes: New analogues for the treatment of Alzheimer, glaucoma and epileptic diseases.

Bioorganic chemistry, 101:104066.

The interaction of the coordination compounds with biological molecules resulted in the investigation of the drug potential of these molecules. In this study, enzyme inhibition of DSA (1-3) coordination compounds that were previously investigated for their anticancer and antibacterial properties was investigated. Also, DSA (1-3) had Ki values of 635.30 + 152.62, 184.01 + 90.05, and 163.03 ± 60.01 µM against human carbonic anhydrase I, 352.23 ± 143.09, 46.2 ± 15.47, and 54.117 ± 18.80 µM against AChE, 310.64 ± 97.35, 35.54 ± 7.01, and 101.51 ± 15.314 µM against BChE, respectively. The biological activity values of these compounds against enzymes whose name are AChE, BChE, and hCAI were compared. Ellman and Verporte methods were used for the study of these enzymes. Cholinesterase inhibitors, also known as anti-cholinesterase and cholinesterase blocking drugs, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. They may be used as drugs for Alzheimer's and myasthenia gravis. It is a common method for comparing biological activity values of nickel complexes with molecular docking calculations. Nickel complexes were studied against enzymes that are human carbonic anhydrase isozyme I for ID 2CAB (hCA I), butyrylcholinesterase for ID 1P0I (BChE), and acetylcholinesterase for ID 1EEA (AChE), respectively.

RevDate: 2020-08-14

Liu B, Cao Y, Shi F, et al (2020)

The overexpression of RBM3 alleviates TBI-induced behaviour impairment and AD-like tauopathy in mice.

Journal of cellular and molecular medicine [Epub ahead of print].

The therapeutic hypothermia is an effective tool for TBI-associated brain impairment, but its side effects limit in clinical routine use. Hypothermia up-regulates RNA-binding motif protein 3 (RBM3), which is verified to protect synaptic plasticity. Here, we found that cognitive and LTP deficits, loss of spines, AD-like tau pathologies are displayed one month after TBI in mice. In contrast, the deficits of LTP and cognitive, loss of spines and tau abnormal phosphorylation at several sites are obviously reversed in TBI mice combined with hypothermia pre-treatment (HT). But, the neuroprotective role of HT disappears in TBI mouse models under condition of blocking RBM3 expression with RBM3 shRNA. In other hand, overexpressing RBM3 by AAV-RBM3 plasmid can mimic HT-like neuroprotection against TBI-induced chronic brain injuries, such as improving LTP and cognitive, loss of spines and tau hyperphosphorylation in TBI mouse models. Taken together, hypothermia pre-treatment reverses TBI-induced chronic AD-like pathology and behaviour deficits in RBM3 expression dependent manner, RBM3 may be a potential target for neurodegeneration diseases including Alzheimer disease.

RevDate: 2020-10-12

Azib L, Debbache-Benaida N, Da Costa G, et al (2020)

Neuroprotective effects of Fraxinus angustifolia Vahl. bark extract against Alzheimer's disease.

Journal of chemical neuroanatomy, 109:101848.

Alzheimer disease's (AD) is a neurodegenerative disease induced by amyloid-β (Aβ) aggregation and accumulation of neurotoxic metals in the brain. Fraxinus angustifolia Vahl. (Oleaceae) is a Mediterranean plant traditionally used to treat several human problems as nervous system problems. This study aimed to evaluate the neuroprotective effects of F. angustifolia Vahl. bark extract (FAB) in vitro and in vivo against Aβ-aggregation and aluminium induced-neurotoxicity in mice. FAB was characterized by colorimetric methods and its individual compounds were identified and quantified by LC-MS. First, the neuroprotective effect of FAB was evaluated against Aβ25-35-aggregation where it was directly incubated with Aβ25-35 and the kinetic of aggregation was measured by spectrophotometer at 200 nm. Then, the extract was tested against Aβ25-35-induced cytotoxicity on PC12 cells and the cells viability was determined by MTT test. On the other hand, FAB (0.01-0.5 mg/mL) was tested against aluminium-activated lipid peroxidation in mice synaptosomal membranes, and in vivo against aluminium-caused neurotoxicity in male N.M.R.I. (Naval Medical Research Institute) mice; this test consisted of daily co-administration of the extract with Al for 60 days. At the end of the treatment, behavioral and memory tests (locomotor activity, black and white and Morris water maze tests) and histological analysis were realized. The identification and quantification of FAB phenolics revealed the presence of different phenolic classes with high concentration of phenylethanoids and hydroxycoumarins. FAB showed a high Aβ25-35 anti-aggregative effect and a dose dependent protective effect on PC12 cells. The extract also demonstrated a significant inhibition of lipid peroxidation and was found to prevent the Al harmful effects where it significantly increased the locomotor activity, decreased the anxiety, improved memory and reduced histological alterations. In conclusion, FAB is rich of bioactive compounds that gave it the ability to inhibit Aβ-aggregation and Al-caused neurotoxicity in mice.

RevDate: 2020-09-28

Ghanbari-Maman A, Ghasemian-Roudsari F, Aliakbari S, et al (2019)

Calcium Channel Blockade Ameliorates Endoplasmic Reticulum Stress in the Hippocampus Induced by Amyloidopathy in the Entorhinal Cortex.

Iranian journal of pharmaceutical research : IJPR, 18(3):1466-1476.

Entorhinal cortex (EC) is one of the first cerebral regions affected in Alzheimer's disease (AD). The pathology propagates to neighboring cerebral regions through a prion-like mechanism. In AD, intracellular calcium dyshomeostasis is associated with endoplasmic reticulum (ER) stress. This study was designed to examine hippocampal ER stress following EC amyloidopathy. Aβ1-42 was bilaterally microinjected into the EC under stereotaxic surgery. Rats were daily treated with 30 μg of isradipine, nimodipine, or placebo over one week. Passive avoidance and novel object recognition (NOR) tasks were performed using shuttle box and NOR test, respectively. GRP78/BiP and CHOP levels were measured in the hippocampal dentate gyrus (DG) by western blot technique. The glutathione (GSH) level and PDI activity were also assessed in the hippocampus by colorimetric spectrophotometer. Aβ treated group developed passive avoidance and novel recognition memory deficit compared to the control group. However, treatment with calcium channel blockers reversed the impairment. BiP and CHOP level increased in the hippocampus following amyloidopathy in the EC. PDI activity and GSH level in the hippocampus decreased in the Aβ treated group, but calcium channel blockers restored them toward the control level. In conclusion, memory impairment due to EC amyloidopathy is associated with ER stress related bio-molecular changes in the hippocampus, and treatment with L-type calcium channel blockers may prevent the changes and ultimately improve cognitive performance.

RevDate: 2020-07-09

Kumar R, Gulati M, Singh SK, et al (2020)

Road From Nose to Brain for Treatment of Alzheimer: The Bumps and Humps.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-107983 [Epub ahead of print].

Vulnerability of the brain milieu to even the subtle changes in its normal physiology is guarded by a highly efficient blood brain barrier. A number of factors i.e. molecular weight of the drug, its route of administration, lipophilic character etc. play a significant role in its sojourn through the blood brain barrier (BBB) and limit the movement of drug into brain tissue through BBB. To overcome these problems, alternative routes of drug administration have been explored to target the drugs to brain tissue. Nasal route has been widely reported for the administration of drugs for treatment of Alzheimer. In this innovative approach, the challenge of BBB is bypassed. Through this route, both the larger as well as polar molecules can be made to reach the brain tissues. Generally, these systems are either pH dependent or temperature dependent. Results: The present review highlights the anatomy of nose, mechanisms of drug delivery from nose to brain, critical factors in the formulation of nasal drug delivery system, nasal formulations of various drugs that have been tried for their nasal delivery for treatment of Alzheimer. Conclusion: It also dives deep to understand the factors that contribute to the success of such formulations to carve out a direction for this niche area to be explored further.

RevDate: 2020-09-17
CmpDate: 2020-09-17

Zhang R, Zhang JL, Li BT, et al (2020)

[Study on mechanisms of anti-Alzheimer's disease action of absorbed components of Gardeniae Fructus based on network pharmacology].

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 45(11):2601-2610.

Gardeniae Fructus has the traditional effects of promoting intelligence and inducing resuscitation, but its mechanism is unclear. In this study, the relationship between Gardeniae Fructus's traditional effect of promoting intelligence and inducing resuscitation and anti-Alzheimer's disease effect was taken as the starting point to investigate the anti-Alzheimer's disease mechanism of the major absorbed components in Gardeniae Fructus by the network pharmacology method. The network pharmacology research model of &quot;absorbed composition-target-pathway-disease&quot; was adopted. In this study, the active components screening and target prediction technology were used to determine the active components and targets of Gardeniae Fructus in treatment of Alzheimer's disease. The enrichment pathway and biological process of Gardeniae Fructus were studied by using the bioinformatics annotation database(DAVID), and the results of molecular docking validation network analysis were used to elaborate the mechanism of Gardeniae Fructus in treatment of Alzheimer's disease. It was found that 35 absorbed components of Gardeniae Fructus not only regulated 48 targets such as cholines-terase(BCHE) and carbonic anhydrase 2(CA2), but also affected 11 biological processes(e.g. transcription factor activity, nuclear receptor activity, steroid hormone receptor activity, amide binding and peptide binding) and 7 metabolic pathways(MAPK signaling pathway, Alzheimer disease and estrogen signaling pathway, etc.). Molecular docking results showed that more than 60% of the active components could be well docked with key targets, and the relevant literature also showed that the active components could inhibit the MAPK1 expression of key targets, indicating a high reliability of results. These results indicated that Gardeniae Fructus may play its anti-Alzheimer's disease action via a &quot;multi-ingredients-multi-targets and multi-pathways&quot; mode, providing a scientific basis for further drug research and development.

RevDate: 2020-09-28

Zhao T, Hu Y, Zang T, et al (2020)

Identifying Protein Biomarkers in Blood for Alzheimer's Disease.

Frontiers in cell and developmental biology, 8:472.

Background: At present, the main diagnostic methods for Alzheimer's disease (AD) are positron emission tomography (PET) scanning of the brain and analysis of cerebrospinal fluid (CSF) sample, but these methods are expensive and harmful to patients. Recently, more researchers focus on diagnosing AD by detecting biomarkers in blood, which is a cheaper and harmless way. Therefore, identifying AD-related proteins in blood can help treatment and diagnosis. Methods: We proposed a hypothesis that similar diseases share similar proteins. Diseases with similar symptoms are caused by abnormalities of similar proteins. Assuming that the similarities between AD and other diseases obey the normal distribution, we developed an iterative method based on disease similarity (IBDS). We combined Elastic Network (EN) with Minimum angle regression (MAR) to find the optimal solution. Finally, we used case studies and Summary data Mendelian Random (SMR) to verify our method. Results: We selected 39 diseases which are highly related to AD. They correspond 1,481 kinds of proteins. One hundred and eighty-four proteins are reported to be related to AD in Uniprot and the number would be 284 with our method. The AUC of our method by cross-validation is 0.9251 which is much higher than previous methods. Conclusion: In this paper, we presented a novel method for prioritizing AD-related proteins. Seven proteins have tissue specificity in blood among these 284 proteins, which could be used to diagnose AD in future. Case studies and SMR have been used to prove the relationship between these 7 proteins and AD. Availability and Implementation: https://github.com/zty2009/Identifying-Protein-Biomarkers-in-Blood-for-Alzheimer-s-Disease.

RevDate: 2020-09-28

Jahangard Y, Monfared H, Moradi A, et al (2020)

Therapeutic Effects of Transplanted Exosomes Containing miR-29b to a Rat Model of Alzheimer's Disease.

Frontiers in neuroscience, 14:564.

Alzheimer disease (AD) is a complex neurodegenerative disorder with no definite treatment. The expression of miR-29 family is significantly reduced in AD, suggesting a part for the family members in pathogenesis of the disease. The recent emergence of microRNA (miRNA)-based therapeutic approaches is emphasized on the efficiency of miRNA transfer to target cells. The endogenously made secretory vesicles could provide a biological vehicle for drug delivery. Characteristics such as small sizes, the ability to cross the blood-brain barrier, the specificity in binding to the right target cells, and most importantly the capacity to be engineered as drug carriers have made exosomes desirable vehicles to deliver genetic materials to the central nervous system. Here, we transfected rat bone marrow mesenchymal stem cells and HEK-293T cells (human embryonic kidney 293 cells) with recombinant expression vectors, carrying either mir-29a or mir-29b precursor sequences. A significant overexpression of miR-29 and downregulation of their targets genes, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and BIM [Bcl-2 interacting mediator of cell death (BCL2-like 11)], were confirmed in the transfected cells. Then, we confirmed the packaging of miR-29 in exosomes secreted from the transfected cells. Finally, we investigated a possible therapeutic effect of the engineered exosomes to reduce the pathological effects of amyloid-β (Aβ) peptide in a rat model of AD. Aβ-treated model rats showed some deficits in spatial learning and memory. However, in animals injected with miR-29-containing exosomes at CA1 (cornu ammonis area), the aforementioned impairments were prevented. In conclusion, our findings provide a new approach for the packaging of miR-29 in exosomes and that the engineered exosomes might have a therapeutic potential in AD.

RevDate: 2020-10-09

Shi Y, Zhang L, Gao X, et al (2020)

Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.

Journal of Alzheimer's disease : JAD, 76(4):1375-1389.

BACKGROUND/OBJECTIVE: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice.

METHODS: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration.

RESULTS: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice.

CONCLUSIONS: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.

RevDate: 2020-08-05
CmpDate: 2020-08-05

Bhandari RK, Wang X, Saal FSV, et al (2020)

Transcriptome analysis of testis reveals the effects of developmental exposure to bisphenol a or 17α-ethinylestradiol in medaka (Oryzias latipes).

Aquatic toxicology (Amsterdam, Netherlands), 225:105553.

Endocrine disrupting chemicals (EDCs) can induce abnormalities in organisms via alteration of molecular pathways and subsequent disruption of endocrine functions. Bisphenol A (BPA) and 17α-ethinylestradiol (EE2) are ubiquitous EDCs in the environment. Many aquatic organisms, including fish, are often exposed to varying concentrations of BPA and EE2 throughout their lifespan. Both BPA and EE2 can activate estrogenic signaling pathways and cause adverse effects on reproduction via alteration of pathways associated with steroidogenesis. However, transcriptional pathways that are affected by chronic exposure to these two ubiquitous environmental estrogens during embryonic, larval, and juvenile stages are not clearly understood. In the present study, we examined transcriptional alterations in the testis of medaka fish (Oryzias latipes) chronically exposed to a low concentration of BPA or EE2. Medaka were exposed to BPA (10 μg/L) or EE2 (0.01 μg/L) from 8 h post-fertilization (as embryos) to adulthood 50 days post fertilization (dpf), and transcriptional alterations in the testis were examined by RNA sequencing (RNA-seq). Transcriptomic profiling revealed 651 differentially expressed genes (DEGs) between BPA-exposed and control testes, while 1475 DEGs were found between EE2-exposed and control testes. Gene ontology (GO) analysis showed a significant enrichment of "intracellular receptor signaling pathway", "response to steroid hormone" and "hormone-mediated signaling pathway" in the BPA-induced DEGs, and of "cilium organization", "microtubule-based process" and "organelle assembly" in the EE2-induced DEGs. Pathway analysis showed significant enrichment of "integrin signaling pathway" in both treatment groups, and of "cadherin signaling pathway", "Alzheimer disease-presenilin pathway" in EE2-induced DEGs. Single nucleotide polymorphism (SNP) and insertion-deletion (Indel) analysis found no significant differences in mutation rates with either BPA or EE2 treatments. Taken together, global gene expression differences in testes of medaka during early stages of gametogenesis were responsive to chronic BPA and EE2 exposure.

RevDate: 2020-07-03

Alam J, Jaiswal V, L Sharma (2020)

Screening of Antibiotics against β-amyloid as Anti-amyloidogenic Agents: A Drug Repurposing Approach.

Current computer-aided drug design pii:CAD-EPUB-107878 [Epub ahead of print].

BACKGROUND: β-amyloid (Aβ) production and aggregation is the main culprit of Alzheimer's disease (AD). AD is becoming crisis where no treatment available for halting the disease progression. Antibiotics are used not only to treat infections, but also some of the non-contagious diseases and have found active as anti-amyloidogenic agents.

OBJECTIVE: The work aim's to investigate anti-amyloidogenic activity of antibiotics as re-purposing agents via inhibiting Aβ aggregation and fibril formation employing in-silico and in-vitro approaches. Mehtods: In-silico screening was designed with receptor and ligand preparation, grid formation, docking simulation and its analysis. Thioflavin T-amyloid binding and protease-digestion studies were intended as in-vitro assays. The pharmacological potential of antibiotics as anti-amyloidogenic agents was assessed by these methods.

RESULTS: Paromomycin and Neomycin were identified with higher order of estimated free energy of binding in in-silico sreening. In in-vitro screening, paromomycin significantly (p<0.01) reduced the fluorescence intensity and resistance to tryptic degradation of Aβ(1-42) peptides while neomycin had no or little effect (p<0.01) when compared to control. Results from docking and wet lab studies were found in correlation.

CONCLUSION: Paromomycin exhibited higher anti-Aβ aggregating and defibrillogenic activity than neomycin and leaves an indication for further in-vivo testing and could be a future promising anti-amyloidal candidate for the treatment of several amyloidoses.

RevDate: 2020-10-08

Schwartz L, Peres S, Jolicoeur M, et al (2020)

Cancer and Alzheimer's disease: intracellular pH scales the metabolic disorders.

Biogerontology, 21(6):683-694.

Alzheimer's disease (AD) and cancer have much in common than previously recognized. These pathologies share common risk factors (inflammation and aging), with similar epidemiological and biochemical features such as impaired mitochondria. Metabolic reprogramming occurs during aging and inflammation. We assume that inflammation is directly responsible of the Warburg effect in cancer cells, with a decreased oxidative phosphorylation and a compensatory highthroughput glycolysis (HTG). Similarly, the Warburg effect in cancer is thought to support an alkaline intracellular pH (pHi), a key component of unrelenting cell growth. In the brain, inflammation results in increased secretion of lactate by astrocytes. The increased uptake of lactic acid by neurons results in the inverse Warburg effect, such as seen in AD. The neuronal activity is dampened by a fall of pHi. Pronounced cytosol acidification results in decreased mitochondrial energy yield as well as apoptotic cell death. The link between AD and cancer is reinforced by the fact that treatment aiming at restoring the mitochondrial activity have been experimentally shown to be effective in both diseases. Low carb diet, lipoic acid, and/or methylene blue could then appear promising in both sets of these clinically diverse diseases.

RevDate: 2020-07-02

Lau YCC, Ding JA, Simental A, et al (2020)

Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Epub ahead of print].

Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )